CN105399685B - The alternatively preparation method and applications of the heteroaromatic compounds of property JAK3 and/or JAK1 kinase inhibitors - Google Patents

The alternatively preparation method and applications of the heteroaromatic compounds of property JAK3 and/or JAK1 kinase inhibitors Download PDF

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CN105399685B
CN105399685B CN201410471468.9A CN201410471468A CN105399685B CN 105399685 B CN105399685 B CN 105399685B CN 201410471468 A CN201410471468 A CN 201410471468A CN 105399685 B CN105399685 B CN 105399685B
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CN105399685A (en
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鲁先平
余金迪
杨千姣
李志斌
潘德思
山松
朱江飞
王祥辉
刘湘衡
宁志强
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Shenzhen microbiology Polytron Technologies Inc
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SHENZHEN WEIXIN BIOLOGICAL SCIENCE AND TECHNOLOGY Co Ltd
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Priority to PL15842179T priority patent/PL3196194T3/en
Priority to PCT/CN2015/089499 priority patent/WO2016041472A1/en
Priority to RSP20191336 priority patent/RS59467B1/en
Priority to JP2017533675A priority patent/JP6516305B2/en
Priority to US15/510,758 priority patent/US10011571B2/en
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to a kind of heteroaromatic compounds, its preparation method and its applications.The structure of the compound is as shown in logical formula (I), wherein the definition of each group is as used in the description.These compounds being capable of selective control JAK3 and/or JAK1 kinases.The compounds of this invention can be used for treating or preventing and the relevant disease of these abnormal kinases, such as autoimmune disease, inflammation disease, cancer and Other diseases.

Description

The alternatively system of the heteroaromatic compounds of property JAK3 and/or JAK1 kinase inhibitors Preparation Method and its application
Technical field
The invention belongs to pharmaceutical technology fields, are related to janus kinase 3 (JAK3) and/or Janus kinases 1 (JAK1) The heteroaromatic compounds of inhibitory activity, preparation method the invention further relates to the compound include the compound as living The pharmaceutical composition of property ingredient and its pharmacy application.The compound of the present invention can be as the inhibition of JAK3 and/or JAK1 kinases Agent, for treating/preventing the clinical practice with these abnormal kinase relevant diseases, including autoimmune disease, inflammation Disease, cancer and Other diseases.
Background technology
2002, Manning et al. determined that human kinase group includes 518 kinds of protein kinase genes, wherein 218 kinds of enzymes Occurrence and development closely related (Manning G., the et al.2002, Science, 298 of gene and human diseases：1912- 1934).In the drug having now been found that, the drug using enzyme as action target spot accounts for as many as 20%, is especially targeted protein kinase There is special value in clinical practice.
Protein kinase is that a kind of intracellular messenger relies on, and is catalyzed specific protein phosphorylation and completes signal transduction process Enzyme, mainly including tyrosine protein kinase (JAKs, Src, Abl, EGFR, FGFR, PDGFR etc.), serine/threonine protein kinase Enzyme (PKC, MAPK, Rho kinases etc.), dual specificity protein kinases (MAPKK) and phosphatidyl inositol kinase (PI3K).Albumen swashs Enzyme phosphorylation/dephosphorylation process can adjust the various biological process of different cells, and such as metabolism, cell differentiation, cell are deposited (Shchemelinin I., the et al.2006, Folia such as work, Apoptosis, orga- nogenesis, angiogenesis, immune response Biol., 52：81-100).
Jak kinase (Janus kinase, abbreviation JAKs, including four known member JAK3, JAK1, TYK2, JAK2) is A Ge little families in endochylema in non-receptor tyrosine protein kinase superfamily.JAK3 is distributed in marrow and lymphatic system, JAK1, TYK2, JAK2 are then distributed widely in Various Tissues cell.When JAKs is attached to the cytokine receptor of cell surface Afterwards, the JAKs of activated receptor coupling, and then make receptor phosphorylation, this is endochylema signal transduction and activating transcription factor stat protein (Signal Transducers and Activators of Transcription, STAT1~4, STAT5a, STAT5b, STAT6 recruitment site) is provided, JAKs phosphorylation stat proteins are transferred to regulation and control base in nucleus after the latter's dimerization Because of expression, this approach, that is, JAK/STAT signal paths (O ' Shea J.J., et al.2013, N.Engl.J.Med., 368： 161-170)。
JAK/STAT signal paths are a signal transduction pathways stimulated by cytokine profiles and growth factor receptors, These factors include interleukin class (IL-2~7, IL-9, IL-10, IL-15, IL-21), interferons (IFN-α, IFN-β, IFN-γ), hematopoietin (EPO), granulocyte and giant cell colony stimulating factor (GM-CSF), somatotropin (GH), Prolactin (PRL), thrombopoietin (TPO) etc. are participating in multiplication, the immunological regulation of immunocyte and candidate stem cell Biological process in play a crucial role (Ghoreschi K., et al.2009, Immunol.Rev., 228：273-287).No Isoacceptor can activate the jak kinase of different subtype, so as to fulfill the biological function of differentiation.
JAK1 can in IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, gp130 families IL-6 and other receptors etc. of the c containing γ combine (Rodig S.J., et al.1998, Cell, 93：373-383).Mouse mould JAK1 gene knockout experiments in type show that the enzyme plays pass in the biological effect for adjusting above-mentioned cytokine profiles receptor Key acts on (Kisseleva T., et al.2002, Gene, 285：1-24).JAK1 is immune correlated disease, inflammation and cancer etc. The new target spot of disease areas.JAK1 inhibitor can be used for treating/prevention of autoimmune diseases, inflammation and tumour (Hornakova T., et al.2010, Blood, 115：3287-3295), such as leukaemia, lymthoma, melanoma, joint Inflammation, psoriasis, Crohn disease, lupus erythematosus, Immune Deficiency Syndrome, Behcet's disease (Hou S., et al.2013, Hum.Genet., 132：1049-1058) etc., but it is not limited to this.
JAK2 plays important work during the adjusting including a variety of receptor signals such as EPO, GH, PRL, IL-3, IFN-γ With (Kisseleva T., et al.2002, Gene, 285：1-24；Levy D.E., et al.2002, Nat.Rev.Mol.Cell Biol., 3：651-662；O ' Shea J.J., et al.2002, Cell, 109 (suppl.)： S121-S131).In mouse model knock out JAK2 can cause anaemia animal dead (Schindler C., et al.2007, J.Biol.Chem., 282：20059-20063)；A base mutation JAK2V617F on JAK2 genes in human body, with Polycythemia vera (PV), essential thrombocythemia (ET) in myeloproliferative disease, idiopathic myelofibrosis Change (IMF), the generation of chronic myelocytic leukemia (CML) etc. it is closely related (Ghoreschi K., et al.2009, Immunol.Rev., 228：273-287).Therefore, JAK2 has become the definite action target spot for the treatment of/prevention of such disease.
JAK3 with the γ in the cytokine receptor complex such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 by being total to Chain (γ c) is combined, and adjusts cellular signal transduction.JAK3 or γ c mutation can all cause severe combined immunodeficiency (SCID) (Villa A., et al.1996, Blood, 88：817-823).JAK3 activity Novel presentation largely subtracts for T cell and NK cells Less, B cell function is lost, and seriously affects the natural biological function of immune system etc..Based on its functional characteristics and special group Distribution is knitted, JAK3 becomes for the very attractive drug target of immune system relevant disease, and inhibitor is closed in rheumatoid Section scorching (RA), Crohn disease, systemic loupus erythematosus, multiple sclerosis, type-1 diabetes mellitus, psoriasis, anaphylactia, heavy breathing Have in terms of asthma, chronic obstructive pulmonary disease, leukaemia, lymthoma, organ transplant and the treatment of the diseases such as other/prevention important Clinical value (Papageorgiou A.C., et al.2004, Trends Pharm.Sci., 2004,25：558-562).
TYK2 is first member in JAK families, can be disturbed plain (IFNs), IL-10, IL-6, IL-12, IL- 23rd, a variety of receptor activations such as IL-27.In mouse, TYK2 afunction can cause the signal path of cytokine profiles receptor Generation defect, and then cause virus infection, antibacterial immunity function reduction and add possibility of pulmonary infection etc. (Kisseleva T., et al.2002, Gene, 285：1-24).In addition, the research of Larner A.C. groups shows that TYK2 can Contribute to inhibit breast cancer growth and transfer (Zhang Q., et al.2011, J.Interferon Cytokine Res., 31：671-677)；The seminar is it has recently been reported that TYK2 can pass through the differentiation of brown adipose tissue (BAT) in mouse and human body And the fat achievement in research adjusted is assisted, body can be protected from obesity or even obesity (Derecka M., et can be reversed Al.2012, Cell Metab., 16：814-824).This perhaps provides new chance for fat cancer patient's treatment.
In November, 2012, the pan-JAKs inhibitor Xeljanz (Tofacitinib) of Pfizer companies obtain FDA approvals and use In treatment RA.In October, 2013, the said firm disclose Xeljanz for treating the III clinical datas of psoriasis, compare Enbrel (Etanercept) double-blind trial, the drug meet Noninferior solution design studies result.Include however, Xeljanz has Cause the side effects such as red blood cell declines with quantity of leucocyte, cholesterol levels rise, this perhaps inhibits to live with it with high JAK2 Property but selectivity relatively low correlation (Zak M., et al.2012, J.Med.Chem., 55：6176-6193).Therefore, it is necessary to study And find selective JAK inhibitor.
It there is now multiple choices JAK inhibitor and be in different clinical investigation phases, including selective JAK 3 restrainer VX-509, selectivity JAK1 inhibitor GLPG0634 (Feist E., et al.2013, Rheumatology, 52：1352- 1357) and INCB39110 (http://www.incyte.com/research/pipeline) etc., for treating RA, Crow grace The immune systems relevant disease such as disease, psoriasis, myelofibrosis.In addition, the selective depression of a variety of different types of structure The related patents of agent are disclosed：1) selective JAK 3 restrainer, such as pyrrolo- [1,2-b] pyridazine (WO2012125887), pyrazoles And [3,4-d] pyrimidine (WO2011048082, WO2011134861, WO2012022681), diaminopyrimidine (WO2011029807, WO2012015972), pyrrolo- [2,3-b] pyridine (JP2012012332), diamino-pyridine -3- first Amide (WO2010061971, US20120108566), pyrrolo- [2,3-b] pyrazine (WO2011144584, WO2011144585) Deng；2) selectivity JAK1 inhibitor, such as tricyclic compounds (WO2011086053), the pyrazoles of substitution and pyroles (WO2010135650, WO2011112662), anilino- phthalazines class (WO2012037132) etc..In addition, with selectivity JAK2 Inhibitor, selectivity TYK2 inhibitor and simultaneously tool there are two types of hypotype (JAK3/1, JAK1/2 etc.) inhibitor related patents Also it has been reported, details are not described herein.
ITK (Inducible T-cell kinase) is one of nonreceptor tyrosine kinase in Tec families, also known as Emt Or Tsk.ITK is expressed in T cell, NKT cells and mast cell.The kinases is in T cell receptor (TCR), CD28, CD2, chemotactic The signal path of factor acceptor CXCR4 and Fc ε R etc. plays key effect during adjusting, and differentiation and multiplication to T cell etc. have Material impact.The secretion of Th2 type cytokines (including IL-4, IL-5, IL-13 etc.) has during immune inflammation is adjusted Important function, ITK defective effect Th2 cell responses, so as to reduce the reaction of chronic or late phase inflammation (Sahu N., et Al.2009, Curr.Top.Med.Chem., 9：690-703；Lin T.A., et al.2004, Biochemistry, 43： 11056-11062).BLK (B-cell lymphocyte kinase) is one of nonreceptor tyrosine kinase in Src families, It is expressed in bone-marrow-derived lymphocyte, growth and differentiation to bone-marrow-derived lymphocyte etc. are related.BLK kinases, phosphate and it is corresponding jointly by Combining closely between body plays a significant role during the signal path of B-cell receptor (BCR) is adjusted, as the kinases can shadow Ring BCR apoptosis and generation retardance (Texido G., et al.2000, Mol.Cell Biol., 20：1227-1233).BLK exists Also play an important roll in the activation of pre-B cell receptor mediation NF- κ B (Saijo K., et al.2003, Nat.Immunol., 4：274-279).Recent studies have shown that BLK and RA, systemic loupus erythematosus and other various autoimmune diseases Pathogenesis correlation (Simpfendorfer KR., et al.2012, Hum.Mol.Genet., 21：3918-3925；Génin E., et al.2013, PLoS One, 8：e61044).
TBK1 (TANK-binding kinase1) is a kind of Ser/Thr protein kinases in IKK families, also referred to as NAK (NF- κ B activating kinase) or T2K.TBK1 is wide in the stomach of mouse, colon, lung, thymus gland and liver etc. General expression；There is expression in the lymph and non-lymphoid organ of people simultaneously, including spleen, brain and kidney etc..The kinases is to thin The expression of the immune response, inflammation-related factor of bacterium and virus all has adjustment effect, such as IL-6, TNF-α and IFN-β. In insulin signaling pathway, the phosphorylation and lipid metaboli of Ser994 on insulin receptor is adjusted in TBK1.These results indicate that TBK1 played in different immuno-biologies and immunopathology mechanism key effect (Yu T., et al.2012, Mediators Inflamm., 2012：979105-979112；Hammaker D., et al.2012, Rheumatology, 51： 610-618)。
VEGFR (Vascular endothelial growth factor receptor) family includes VEGFR-1 (Flt1), 3 members of VEGFR-2 (KDR/Flk1) and VEGFR-3 (Flt4), by the cell for containing 7 immunoglobulin spline structures Outskirt, film area and tyrosine kinase district's groups are into tyrosine kinase activity therein is activated by receptor and ligand binding, ligand Such as VEGFs A-F and placenta growth factor, further cause the various biological effect of cell, such as growth and differentiation in cell In important function (shibuya M., et al.2010, Genes Cancer, 1：1119-1123).In addition research shows VEGFR1 has expression in endothelial cell, monocyte and macrophage of RA patient etc..VEGFA can activate VEGFR1, cause Endothelial cell proliferation and vascularization etc..It is high in synovia of the VEGFA albumen in patient RA, lymph, serum and synovial tissue Expression, VEGFA levels are proportionate with RA diseases.VEGFR2 has expression in the synovial tissue of RA patient.VEGF A, C, D can VEGFR2 signals are activated, increase vascular permeability and vascularization.It is detected in the various kinds of cell that VEGFC thickens synovial membrane internal layer in RA It measures, particularly in perivascular cell and smooth muscle cell.VEGFR3 can be expressed in monocyte, macrophage, some trees Prominent shape cell, the capillary in normal galactophore tissue and neuroendocrine organ etc..The study found that VEGFR3 is in RA, inflammation Property the autoimmune diseases such as enteropathy, ulcer disease and Crohn disease and lymphatic vessel formed in the morbidity of related neoplasms and all have Certain effect, relevant mechanism of action be not yet fully apparent from (D ' Aura Swanson C, et al.2009, Nat.Rev.Rheumatol., 5：317-324；Aoki Y., et al.2005, J.Natl.Cancer Inst., 97：2-3).
Kinases inhibitor disclosed herein can be used for treat and/or prevent RA, psoriasis, Crohn disease, system Property lupus erythematosus, multiple sclerosis, type-1 diabetes mellitus, anaphylactia, chronic obstructive pulmonary disease, asthma, leukaemia, lymph The immune systems relevant disease such as knurl, but it is not limited to this.Meanwhile these compounds or include its drug as active component The clinical efficacy of these diseases can be reached maximization by composition etc. in safe treatment window.
The content of the invention
One aspect of the present invention is related to the heteroaromatic compounds with JAK3 and/or JAK1 inhibitory activity, including its medicine The derivatives such as acceptable salt, hydrate, stereoisomer, prodrug on.
Another aspect of the present invention is related to the preparation method of compound described herein.
Another aspect of the present invention is related to including its compounds of this invention pharmaceutical composition as active component, Yi Jiben Invention compound or pharmaceutical composition are used to treating/prevent the clinical practice with the relevant disease of abnormal kinases such as JAKs, And the compounds of this invention or pharmaceutical composition prepare to treat and/or prevent it is relevant with the abnormal kinases such as JAKs Application in the drug of disease.
The present invention relates to logical formula (I) compound represented, including its prodrug, stereoisomer, pharmaceutically acceptable salt Or hydrate,
Wherein,
R1For halogen or C1-C6 alkyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxies, C1- The halogenated alkyl of C6, the alkyl-carbonyl of C1-C6 and C1-C6 alkyl aminos；
R3For hydrogen or halogen；
R4For hydrogen or C1-C4 alkyl；
X is NH, O or S；
Y is CO or S (O)2；
Z is covalent bond, CH2Or (CH2)2；
N is 1 to 4 integer；
Ring A is phenyl ring, pyridine ring or piperidine ring.
At a preferred aspect, the present invention relates to logical formula (I) compound represented, including its prodrug, stereoisomer, Pharmaceutically acceptable salt or hydrate, wherein,
R1For halogen or C1-C6 alkyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, fluorine, methyl, ethyl, methoxyl group, difluoromethyl, three Methyl fluoride, acetyl group and dimethylamino；
R3For hydrogen or halogen；
R4For hydrogen or methyl；
X is NH or O；
Y is CO or S (O)2；
Z is covalent bond, CH2Or (CH2)2；
N is 1 to 4 integer；
Ring A is phenyl ring, pyridine ring or piperidine ring.
In terms of one preferred, the present invention relates to logical formula (I) compound represented, including its prodrug, alloisomerism Body, pharmaceutically acceptable salt or hydrate, wherein,
R1For halogen or C1-C6 alkyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, fluorine, methyl, ethyl, methoxyl group, difluoromethyl, three Methyl fluoride, acetyl group and dimethylamino；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is 1 to 4 integer；
Ring A is phenyl ring, pyridine ring.
In terms of one preferred, the present invention relates to logical formula (I) compound represented, including its prodrug, alloisomerism Body, pharmaceutically acceptable salt or hydrate, wherein,
R1For chlorine, fluorine or methyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, fluorine, methyl, ethyl, methoxyl group, difluoromethyl, three Methyl fluoride, acetyl group and dimethylamino；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is 1 to 4 integer；
Ring A is phenyl ring.
One even more preferably from terms of, the present invention relates to logical formula (I) compound represented, including its prodrug, three-dimensional different Structure body, pharmaceutically acceptable salt or hydrate, wherein,
R1For chlorine；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, fluorine, methyl, ethyl, methoxyl group, difluoromethyl, three Methyl fluoride, acetyl group and dimethylamino；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is 1 to 4 integer；
Ring A is phenyl ring.
It is different including its prodrug, solid the present invention relates to logical formula (I) compound represented in a particularly preferred aspect Structure body, pharmaceutically acceptable salt or hydrate, wherein,
R1For chlorine；
R2For one or more substituent groups, selected from cyano, fluorine and trifluoromethyl；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is equal to 1；
Ring A is phenyl ring.
It is different including its prodrug, solid the present invention relates to logical formula (I) compound represented at an especially preferred aspect Structure body, pharmaceutically acceptable salt or hydrate, wherein,
R1For chlorine；
R2For one or more substituent groups, selected from cyano；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is equal to 1；
Ring A is phenyl ring.
Description of the drawings
Fig. 1 is the schematic diagram for showing Z '-LYTE kinase activity testing principles, is swashed that reflects involved in detection process Enzyme-to-substrate reaction occurs chromogenic reaction and is detected.
Specific embodiment
" halogen " of the present invention is fluorine, chlorine, bromine, especially iodine, fluorine, chlorine or bromine.
" alkyl " of the present invention, including straight chain, branch or cricoid alkyl.Preferably, the alkyl is C1-C8 alkane Base, C1-C6 alkyl；Particularly preferred, the alkyl is C1-C4 alkyl；It is particularly preferred, the alkyl is methyl, ethyl, Propyl or isopropyl, normal-butyl, isobutyl group or tertiary butyl (tertiary butyl).Alkyl in the compounds of this invention can optionally be substituted Or it is unsubstituted, substituent group can include alkyl, halogen, alkoxy, alkyl, hydroxyl etc..The example of alkyl of the present invention includes first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohesyl, ring third Base, cyclobutyl, cyclopenta, cyclohexyl etc..
" alkoxy " of the present invention refers to that abovementioned alkyl is connected formed group with oxygen atom, wherein, oxygen atom With free bonding power, such as methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, isopropoxy, tert-butoxy, ring third Oxygroup, cyclohexyl oxygroup etc..
" alkyl-carbonyl " of the present invention refers to that abovementioned alkyl is connected formed group with carbonyl, such as acetyl group, third Acyl group, iso-propionyl, bytyry, special bytyry, ring propiono, cyclohexyl acyl group etc..
" alkyl amino " of the present invention refers to that abovementioned alkyl is connected formed group with amino, such as methylamino, second Amido, 4- dimethylaminos etc..
" pharmaceutically useful " of the present invention or " pharmaceutically acceptable " are understood to fit in the range of rational medicine It is used in humans and animals, can tolerate and have no unacceptable side effect includes toxicity, allergic reaction, stimulation and complication and its It.
The present invention relates to pharmaceutical composition, described pharmaceutical composition contains the compound of above-mentioned logical formula (I), including before it Medicine, stereoisomer, pharmaceutically acceptable salt or hydrate are as active ingredient and pharmaceutical acceptable carrier, auxiliary material or figuration Agent etc..Described pharmaceutical acceptable carrier, auxiliary material or excipient refer to any diluent, adjuvant and carrier available for drug field, Such as pharmaceutic adjuvant handbook (Handbook of Pharmaceutical Excipients 8thEd, 2013) listed material in, But it is not limited to this.
Compound of the present invention can optionally be used with other one or more active ingredient combinations, each plant demand According to situations such as specific illness and specific patient and clinical it can be needed and be adjusted by those skilled in the art with ratio.
Compound of the present invention, pharmaceutical composition can be configured to various dosage forms, wherein containing being commonly used in drug field Excipient, such as oral formulations (tablet, capsule, powder, granule, syrup, pill), ejection preparation, topical formulations etc., But it is not limited to this.By weight 0.5~70% active ingredient is usually contained in the dosage form of the present invention, it is preferable that contain There is by weight 1~20% active ingredient.
Compounds of formula I of the present invention, clinically can by oral or injection system to mammal (including People) medication is carried out, wherein being preferred especially with oral way.Dosage be daily 0.0001~200mg/kg weight, preferable medication Dosage is daily 0.01~100mg/kg weight, and optimal dosage is daily 0.1~50mg/kg weight.Meanwhile optimal dose Depending on individual, dosage is smaller when usually starting, and is then gradually increased dosage.
Embodiment and preparation example provided in the present invention further elucidate and compound of the present invention have been illustrated And preparation method thereof.It should be appreciated that the scope of following preparation examples and embodiment does not limit the scope of the invention in any way.
Following synthetic route describes the preparation method of the logical formula (I) derivative of the present invention, following to synthesize in schematic diagram Raw materials used, reagent, catalyst, solvent etc. can be prepared by organic chemistry filed method well-known to the ordinarily skilled artisan or It is available commercially.The all final derivative of the present invention all can all cross the method or its similar approach system described in schematic diagram , these methods are all that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole variable factors applied in these schematic diagrames Definition as defined below or in claim.
Preparation method：
(a) intermediate III (a) can directly be bought by market or be prepared by following exemplary synthetic procedure：
It is condensed the diamines VI and compound VII of unilateral protection and obtains compound VIII.The condensation reaction is with peptide condensing agent For catalyst, such as 1- ethyls -3- (3- dimethylamine propyls) carbodiimide (EDC), N, N '-dicyclohexylcarbodiimide (DCC), N, N '-carbonyl dimidazoles (CDI) etc..Reaction temperature is 0~60 DEG C, when the reaction time is 2~72 small.It is common to react solvent for use Solvent, such as benzene, toluene, tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N '-dimethylformamide etc..If necessary, Alkali, such as sodium hydroxide, triethylamine or pyridine can be added in.
Gained compound VIII takes off Boc under sour (preferably trifluoroacetic acid) effect and obtains compound III (a), reaction temperature 0 ~60 DEG C, when the reaction time is 0.5~2 small.Reaction solvent for use is dichloromethane, tetrahydrofuran, N, N '-dimethylformamide Deng.
(b) intermediate III (b) can directly buy or be prepared by following exemplary synthetic procedure：
It is condensed the diamines VI and compound IX of unilateral protection and obtains compound X, reaction temperature is 0~60 DEG C, during reaction Between for 0.5~2 it is small when.Reaction solvent for use is common solvent, such as benzene, toluene, tetrahydrofuran, dioxane, dichloromethane, chlorine Imitative, N, N '-dimethylformamide etc..Acid binding agent is often with triethylamine, diisopropyl ethyl amine, pyridine etc.；Optionally, nothing can be added in Machine alkali such as NaOH, Na2CO3, NaOAc etc..
Gained compound X takes off Boc under sour (preferably trifluoroacetic acid) effect and obtains compound III (b).Reaction temperature for 0~ 60 DEG C, when the reaction time is 0.5~2 small.Common solvent used in reaction is dichloromethane, tetrahydrofuran, N, N '-dimethyl formyl Amine, water etc..Acid used can be trifluoroacetic acid, hydrochloric acid etc..
(c) intermediate V can be prepared by following exemplary synthetic procedure：
Compound XI (can market buy or synthesize obtain) is made to be deposited with acryloyl chloride in alkali (preferably diisopropyl ethyl amine) Compound XII is condensed to yield under, gained compound XII obtains title intermediate V through iron powder reducing nitro.Alkali used can be with For diisopropyl ethyl amine, triethylamine etc..
(d) logical formula (I) of the present invention can be prepared by following exemplary synthetic procedure：
Make compound II and compound III that substitution reaction occur in the presence of triethylamine and obtain compound IV, wherein chemical combination Object II and III can be by the commercially available reaction temperatures that is commercially available for reflux, when the reaction time is 8-16 small.Reaction solvent for use is second Alcohol, methanol, n-butanol etc..Alkali is triethylamine, diisopropyl ethyl amine etc..
Make compound IV and the compound V of synthesis that substitution reaction occur under sour (preferably trifluoroacetic acid) catalysis and obtain chemical combination Object I.Reaction temperature is reflux, when the reaction time is 8-16 small.Reaction solvent for use is isopropanol, n-butanol etc.；Used in reaction Acid for trifluoroacetic acid, hydrochloric acid etc..
Compound described in general formula I may be employed common separation method and be purified, such as extraction, recrystallization, column chromatography Deng.
Representative compound of the present invention is as shown in table 1.Compound number and " the embodiment volume in embodiment part Number " it is consistent, i.e., in table 1 synthesis of compound 1 described in " embodiment 1 ", the synthesis of compound 30 is " real in table 1 It applies in example 30 " and is described.
1 representative compound of the present invention of table
With reference to the embodiment content that the present invention is furture elucidated, but protection scope of the present invention is not limited only to These examples.Percentage of the present invention is weight percentage in addition to especially indicating.Numerical value model described in this description It encloses, such as measurement unit, reaction condition, compound physical state or percentage, is for providing undoubted desk reference. Those skilled in the art are when implementing the present invention, using outside this scope or being different from the temperature, concentration, number of single number Amount, carbon number etc., in this case it is still possible to obtain expected result.
Embodiment 1
The preparation of the fluoro- N- methyl-5-nitros aniline of 2-
The fluoro- N- methyl-5-nitros aniline of yellow solid 2- (19.0g, 87.0% yield) is prepared by the following method.2- is fluoro- 5- nitroanilines (20.0g, 128.2mmol) and paraformaldehyde (16.0g, 533.3mmol) are dissolved in 500mL methanol at room temperature Stirring.Then the methanol solution 100mL of sodium methoxide (3.4g, 63mmol) is added dropwise.The reaction solution be stirred at room temperature 16 it is small when after Two deciles is divided to add in NaBH4(9.7g, 255.2mmol).Stirring 15 minutes.LC-MS tracking reactions.1M is poured into after reaction In the aqueous solution of KOH, solid is precipitated in stirring.Filtering obtains title intermediate.LC-MS(m/z)171(M+1).
Embodiment 2
The preparation of N- (the fluoro- 5- nitrobenzophenones of 2-)-N methacrylamide
Yellow oil N- (the fluoro- 5- nitrobenzophenones of 2-)-N methacrylamides (12.0g, 83.0% yield) are by as follows It is prepared by method.The fluoro- N- methyl-5-nitros aniline (11.0g, 64.7mmol) of 2- and DIPEA (23mL, 129.4mmol) are dissolved in In 100mL THF, it is stirred at room temperature.Then acryloyl chloride (11mL, 129.4mmol) is added dropwise.The reaction solution is in room temperature Most of solvent is evaporated after when lower stirring 1 is small, adds in the dilution of 100mL ethyl acetate, saturated common salt water washing is dry, and filtering subtracts Pressure concentration obtains title intermediate.LC-MS(m/z)225(M+1).
Embodiment 3
The preparation of N- (5- amino -2- fluorophenyls)-N methacrylamide
Brown oil N- (5- amino -2- fluorophenyls)-N methacrylamides (5.6g, 54.0% yield) are by such as lower section It is prepared by method.Iron powder (20.0g, 357mmol) and NH4Cl (20.0g, 374mmol), which is dissolved in 200mL water, is heated to 80 DEG C of stirrings half Hour.Then the ethyl acetate solution of N- (the fluoro- 5- nitrobenzophenones of 2-)-N methacrylamide (12.0g, 53.6mmol) is added in 20mL.The reaction solution stirred at 80 DEG C 1 it is small when after add in NaHCO3Aqueous solution alkali tune filters iron cement, filtrate ethyl acetate Extraction merges organic pressure of subtracting each other and concentrates acquisition title intermediate.LC-MS(m/z)195(M+1).
Embodiment 4
The preparation of 3- (4- Cyanophenacyls amido) propylcarbamate
White solid 3- (4- Cyanophenacyls amido) propylcarbamate (850mg, 98.0% yield) is by such as It is prepared by lower section method.3- amino propyl aminos t-butyl formate (500mg, 2.87mmol) is dissolved in 20mLTHF, then adds in 1- Ethyl -3- (3- dimethylamine propyls) carbodiimide hydrochloride (1.0g, 5.24mmol), I-hydroxybenzotriazole (580mg, 4.30mmol), DIPEA (1mL, 5.63mmol) and 4- cyanobenzoic acids (425mg, 2.89mmol).Mixture stirs at room temperature Mix 20 it is small when.Then NaHCO is used3Aqueous solution tune pH to 8-10.Ethyl acetate extracts, and merges organic relevant dry, filtering, and decompression is dense Contracting obtains title intermediate.LC-MS(m/z)304(M+1).
Embodiment 5
The preparation of N- (3- aminopropyls) -4- cyanobenzamides
White solid N- (3- aminopropyls) -4- cyanobenzamides (350mg, 62.0% yield) are made by the following method It is standby.3- (4- Cyanophenacyls amido) propylcarbamate (850mg, 2.8mmol) is dissolved in 10mL dichloromethane, then Add in trifluoroacetic acid (500 μ L, 6.7mmol).The reaction solution be stirred at room temperature 16 it is small when after add in NaHCO3Aqueous solution alkali tune, The mixed solution ultrasound of methylene chloride/methanol (10: 1) is added in after being evaporated.Filtrate is evaporated among acquisition target after crossing filter solid Body.LC-MS(m/z)204(M+1).
Embodiment 6
The preparation of 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzamide
White solid N- (3- aminopropyls) -4- cyanobenzamides (3.5g, 78.0% yield) are prepared by the following method. 2,4,5- trichloropyrimidines (2.6g, 14.2mmol), N- (3- aminopropyls) -4- cyanobenzamides (2.6g, 12.8mmol) and Triethylamine (2mL, 14mmol) is dissolved in 50mL ethyl alcohol.The reaction solution be heated to 70 DEG C of stirrings 4 it is small when after react and terminate.Solvent evaporated It is washed afterwards with ether.Filtering obtains title intermediate.LC-MS(m/z)351(M+1).
Embodiment 7
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- cyanobenzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- cyanobenzamides (3.1g, 60.0% yield) are prepared by the following method.N- (3- aminopropyls) -4- cyano Benzamide (4.0g, 11.4mmol), N- (5- amino -2- fluorophenyls)-N methacrylamide (2.7g, 13.9mmol) and three Fluoroacetic acid (1mL, 7mmol) is dissolved in 60mL isopropanols.The reaction solution be heated to 90 DEG C of stirrings 24 it is small when after react and terminate.Reaction solution Pour into NaHCO3In aqueous solution, solid is precipitated.It stands, filtering.Crude product is dissolved in ultrasound in ethyl acetate, filters to obtain target chemical combination Object.1H-NMR(DMSO-d6) δ 1.80-1.83 (m, 2H, CH2), 3.10-3.12 (m, 2H, CH2), 3.32 (s, 3H, CH3), 3.44- 3.46 (m, 2H, CH2), 5.59 (d, J=9.4Hz, 1H, CH), 6.02-6.08 (m, 1H, CH), 6.18 (d, J=16.0Hz, 1H, CH), 7.21-7.23 (m, 1H, Ar-H), 7.26-7.27 (m, 1H, Ar-H), 7.64 (s, 1H, pyrimidine-NH), 7.91 (s, 1H, Ar-H), 7.93 (s, 1H, pyrimidine-H), 7.95-7.96 (m, 2H, Ar-H), 7.97-7.98 (m, 2H, Ar-H), 8.72 (s, 1H, NH), 9.43 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 508 (M+1).
Embodiment 8
The preparation of N- (the fluoro- 5- nitrobenzophenones of 2-) acrylamide
Yellow solid N- (the fluoro- 5- nitrobenzophenones of 2-) acrylamides (0.3g, 71.4% yield) are by the fluoro- 5- nitrobenzenes of 2- Amine (0.3g, 2.0mmol) and acryloyl chloride (0.27g, 3mmol) are prepared according to the similar step in embodiment 2.LC-MS (m/z)211(M+1)。
Embodiment 9
The preparation of N- (5- amino -2- fluorophenyls) acrylamide
Brown solid N- (5- amino -2- fluorophenyls) acrylamides (0.1g, 46.7% yield) are by N- (the fluoro- 5- nitre of 2- Base phenyl) acrylamide (0.25g, 4.7mmol) is prepared according to the similar step in embodiment 3.LC-MS(m/z)181(M +1)。
Embodiment 10
The preparation of 3- (4- trifluoromethyl benzamides base) propylcarbamate
White solid 3- (4- trifluoromethyl benzamides base) propylcarbamate (0.22g, 90% yield) is By 3- amino propyl aminos t-butyl formate (0.4g, 2.4mmol) and 4- trifluoromethylbenzoic acids (0.38g, 2mmol) according to reality The similar step applied in example 4 is prepared.LC-MS(m/z)347(M+1).
Embodiment 11
The preparation of N- (3- aminopropyls) -4- trifluoromethyl benzamides
Yellow liquid N- (3- aminopropyls) -4- trifluoromethyl benzamides (1.1g, 53% yield) are by 3- (4- trifluoros Toluyl amido) propylcarbamate (2.8g, 8mmol) is prepared according to the similar step in embodiment 5. LC-MS(m/z)247(M+1)。
Embodiment 12
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- trifluoromethyl benzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- trifluoromethyl benzamides (1.9g, 57% yield) it is by 2,4,5- trichloropyrimidines (1.46g, 8mmol) and N- (3- aminopropyls) -4- trifluoromethyl benzamides (1.9g, 8mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)393(M+1).
Embodiment 13
N- (3- (2- (3- acrylamido -4- fluoro-phenyls amino) -5- chlorine pyrimidine radicals -4- amino) propyl) -4- fluoroforms The preparation of yl-benzamide
Gray solid N- (3- (2- (3- acrylamido -4- fluoro-phenyls amino) -5- chlorine pyrimidine radicals -4- amino) propyl) - 4- trifluoromethyl benzamides (18mg, 33% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- trifluoros Methyl benzamide (39mg, 0.1mmol) and N- (5- amino -2- fluorophenyls) acrylamide (20mg, 0.11mmol) are according to reality The similar step applied in example 7 is prepared.1H-NMR(DMSO-d6) δ 1.85-1.88 (m, 2H, CH2), 3.32-3.37 (m, 2H, CH2), 3.55-3.58 (m, 2H, CH2), 5.76-5.79 (m, 1H, CH), 6.27-6.32 (m, 1H, CH), 6.61-6.68 (m, 1H, CH), 7.21 (t, J=10.04Hz, 1H, pyrimidine-NH), 7.36-7.40 (m, 1H, Ar-H), 7.82 (d, J=8.16Hz, 2H, Ar-H), 8.02 (d, J=8.1Hz, 2H, Ar-H), 8.16 (s, 1H, pyrimidine-H), 8.28 (s, 1H, Ar-H), 8.37-8.38 (m, 1H, NH), 8.73-8.76 (m, 1H, NH), 9.99 (s, 1H, phenyl ring-NH), 10.28 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 537(M+1)。
Embodiment 14
The preparation of 3- (4- fluorobenzoyls amido) propylcarbamate
White solid 3- (4- fluorobenzoyls amido) propylcarbamate (800mg, 94.1% yield) is by 3- Amino propyl amino t-butyl formate (500mg, 2.87mmol) and 4- fluobenzoic acids (400mg, 2.86mmol) are according to embodiment 4 In similar step be prepared.LC-MS(m/z)297(M+1).
Embodiment 15
The preparation of N- (3- aminopropyls) -4- fluorobenzamides
White solid N- (3- aminopropyls) -4- fluorobenzamides (400mg, 75.2% yield) are by 3- (4- fluorobenzene first Amide groups) propylcarbamate (800mg, 2.70mmol) is prepared according to the similar step in embodiment 5.LC- MS(m/z)197(M+1)。
Embodiment 16
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- fluorobenzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- fluorobenzamides (440mg, 63.2% production Rate) be by 2,4,5- trichloropyrimidines (400mg, 2.19mmol) and N- (3- aminopropyls) -4- fluorobenzamides (400mg, 2.03mmol) it is prepared according to the similar step in embodiment 6.LC-MS(m/z)343(M+1).
Embodiment 17
N- (3- (2- (3- acrylamido -4- fluoro-phenyls amino) -5- chlorine pyrimidine radicals -4- amino) propyl) -4- fluorobenzene first The preparation of amide
White solid N- (3- (2- (3- acrylamido -4- fluoro-phenyls amino) -5- chlorine pyrimidine radicals -4- amino) propyl) - 4- fluorobenzamides (8mg, 9.41% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- fluorobenzoyls Amine (60mg, 0.17mmol) and N- (5- amino -2- fluorophenyls) acrylamide (40mg, 0.22mmol) are according in embodiment 7 Similar step is prepared.1H-NMR(DMSO-d6) δ 1.79-1.83 (m, 2H, CH2), 3.31-3.33 (m, 2H, CH2), 3.49- 3.51 (m, 2H, CH2), 5.75 (d, J=11.2Hz, 1H, CH), 6.26 (d, J=16.99Hz, 1H, CH), 6.55-6.62 (m, 1H, CH), 7.11 (t, J=9.92Hz, 1H, Ar-H), 7.22 (t, J=5.66Hz, 1H, pyrimidine-NH), 7.28 (t, J= 8.73Hz, 2H, Ar-H), 7.47 (t, J=4.93Hz, 1H, Ar-H), 7.88-7.93 (m, 3H, Ar-H, pyrimidine-H), 8.31 (d, J=5.12Hz, 1H, Ar-H), 8.50-8.52 (m, 1H, NH), 9.26 (s, 1H, phenyl ring-NH), 9.85 (s, 1H, phenyl ring-NH) .LC-MS(m/z)487(M+1)。
Embodiment 18
The preparation of N- (3- (the chloro- 5- methylpyrimidines base -4- amino of 2-) propyl) -4- fluorobenzamides
White solid N- (3- (the chloro- 5- methylpyrimidines base -4- amino of 2-) propyl) -4- fluorobenzamides (40mg, 52.3% Yield) it is by 2,4-, bis- chloro- 5- methylpyrimidines (40mg, 0.25mmol) and N- (3- aminopropyls) -4- fluorobenzamides (40mg, 0.20mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)323(M+1).
Embodiment 19
The fluoro- N- of 4- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidine base -4- amino) Propyl) benzamide preparation
The fluoro- N- of white solid 4- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidines Base -4- amino) propyl) benzamide (5mg, 8.68% yield) is by N- (3- (the chloro- 5- methylpyrimidines base -4- amino of 2-) third Base) -4- fluorobenzamides (40mg, 0.12mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (40mg, 0.21mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.80-1.83 (m, 2H, CH2), 1.92 (s, 3H, CH3), 3.19 (s, 3H, CH3), 3.30-3.32 (m, 2H, CH2), 3.42-3.44 (m, 2H, CH2), 5.58- 5.61 (m, 1H, CH), 6.04-6.11 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 6.72 (t, J=5.17Hz, 1H, Ar- H), 7.21 (t, J=9.44Hz, 1H, pyrimidine-NH), 7.28 (t, J=8.8Hz, 2H, Ar-H), 7.66-7.68 (m, 2H, Ar-H, Pyrimidine-H), 7.88-7.92 (m, 2H, Ar-H), 7.98-7.99 (m, 1H, Ar-H), 8.51 (t, J=5.26Hz, 1H, NH), 9.09 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 481 (M+1).
Embodiment 20
The preparation of N- (3- (the chloro- 5- methylpyrimidines base -4- amino of 2-) propyl) -4- trifluoromethyl benzamides
White solid N- (3- (the chloro- 5- methylpyrimidines base -4- amino of 2-) propyl) -4- trifluoromethyl benzamides (0.26g, 72% yield) is by 2,4-, bis- chloro- 5- methylpyrimidines (0.16g, 1mmol) and N- (3- aminopropyls) -4- fluoroforms Yl-benzamide (0.24g, 1mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)373(M+1).
Embodiment 21
N- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidine base -4- amino) third Base) -4- trifluoromethyl benzamides preparation
White solid N- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidine base -4- ammonia Base) propyl) -4- trifluoromethyl benzamides (0.26g, 72% yield) are by N- (3- (the chloro- 5- methylpyrimidines base -4- ammonia of 2- Base) propyl) -4- trifluoromethyl benzamides (75mg, 0.2mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (70mg, 0.3mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.81-1.87 (m, 2H, CH2), 1.93 (s, 3H, CH3), 3.19 (s, 3H, CH3), 3.36-3.38 (m, 2H, CH2), 3.44-3.46 (m, 2H, CH2), 5.58-5.61 (m, 1H, CH), 6.04-6.11 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 6.73 (t, J=5.64Hz, 1H, Ar-H), 7.21 (t, J=9.4Hz, 1H, pyrimidine-NH), 7.66-7.68 (m, 2H, Ar-H, pyrimidine-H), 7.84 (d, J= 8.3Hz, 2H, Ar-H), 7.98-8.00 (m, 1H, Ar-H), 8.03 (d, J=8.1Hz, 2H, Ar-H), 8.71-9.74 (m, 1H, NH), 9.10 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 531 (M+1).
Embodiment 22
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- trifluoromethyl benzamides
Gray solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- trifluoromethyl benzamides (0.23g, 42% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) third Base) -4- trifluoromethyl benzamides (0.39g, 1mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (0.28g, 1.5mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.81-1.84 (m, 2H, CH2), 3.31-3.33 (m, 2H, CH2), 3.45-3.47 (m, 2H, CH2), 5.60 (d, J=9.6Hz, 1H, CH), 6.02-6.08 (m, 1H, CH), 6.18 (d, J=15.1Hz, 1H, CH), 7.25-7.29 (m, 1H, Ar-H), 7.61-7.67 (m, 3H, Ar-H, it is phonetic Pyridine-NH), 7.82-7.84 (m, 3H, Ar-H, pyrimidine-H), 8.00-8.03 (m, 3H, Ar-H, NH), 8.71 (s, 1H, phenyl ring- NH), 9.71 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 551 (M+1).
Embodiment 23
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- fluorobenzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- fluorobenzamides (117mg, 40.3% yield) be by N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) - 4- fluorobenzamides (200mg, 0.58mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (150mg, 0.77mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.78-1.81 (m, 2H, CH2), 3.28-3.29 (m, 2H, CH2), 3.32 (s, 3H, CH3), 3.43-3.45 (m, 2H, CH2), 5.59 (d, J=9.8Hz, 1H, CH), 6.05-6.09 (m, 1H, CH), 6.15-6.20 (m, 1H, CH), 7.22-7.30 (m, 4H, Ar-H), 7.64-7.66 (m, 1H, it is phonetic Pyridine-NH), 7.87-7.91 (m, 3H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.50 (t, J=5.2Hz, 1H, NH), 9.43 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 501 (M+1).
Embodiment 24
The preparation of 3- (1- methyl piperidine base -4- formamidos) propylcarbamate
White solid 3- (1- methyl piperidine base -4- formamidos) propylcarbamate (220mg, 25.6% production Rate) be by 3- amino propyl aminos t-butyl formate (500mg, 2.87mmol) and 1- methyl piperidine -4- carboxylic acids (410mg, 2.87mmol) it is prepared according to the similar step in embodiment 4.LC-MS(m/z)300(M+1).
Embodiment 25
The preparation of N- (3- aminopropyls) -1- methyl piperidine base -4- formamides
White solid N- (3- aminopropyls) -1- methyl piperidine base -4- formamides (130mg, 80.1% yield) are by 3- (1- methyl piperidine base -4- formamidos) propylcarbamate (220mg, 0.74mmol) is according to the class in embodiment 5 It is prepared like step.LC-MS(m/z)200(M+1).
Embodiment 26
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -1- methyl piperidine -4- formamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -1- methyl piperidine -4- formamides (200mg, 79.6% yield) it is by 2,4,5- trichloropyrimidines (130mg, 0.71mmol) and N- (3- aminopropyls) -1- methyl piperidine bases -4- Formamide (130mg, 0.65mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)346(M+1).
Embodiment 27
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 1- methyl piperidine base -4- formamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -1- methyl piperidine base -4- formamides (12mg, 11.6% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- ammonia Base) propyl) -1- methyl piperidine -4- formamides (80mg, 0.23mmol) and N- (5- amino -2- fluorophenyls)-N- methacryls Amine (40mg, 0.20mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.52-1.58 (m, 4H, 2 × CH2), 1.74-1.79 (m, 2H, CH2), 1.96-1.99 (m, 1H, CH), 2.11 (s, 3H, CH3), 3.05-3.12 (m, 4H, 2 × CH2), 3.13-3.16 (m, 4H, 2 × CH2), 3.18 (s, 3H, CH3), 5.60 (d, J=9.7Hz, 1H, CH), 6.03- 6.09 (m, 1H, CH), 6.15-6.21 (m, 1H, CH), 7.25-7.30 (m, 2H, Ar-H, pyrimidine-NH), 7.64-7.69 (m, 1H, Ar-H), 7.76 (t, J=5.45Hz, 1H, NH), 7.84-7.88 (m, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 9.43 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 504 (M+1).
Embodiment 28
N- (3- (2- (3- acrylamido -4- Fluorophenylaminos) -5- chlorine pyrimidine radicals -4- amino) propyl) -4- cyano benzene The preparation of formamide
Black solid N- (3- (2- (3- acrylamido -4- Fluorophenylaminos) -5- chlorine pyrimidine radicals -4- amino) propyl) - 4- cyanobenzamides (20mg, 40% yield) are by 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzene first Amide (35mg, 0.1mmol) and N- (5- amino -2- fluorophenyls) acrylamide (22mg, 0.12mmol) are according in embodiment 7 Similar step is prepared.1H-NMR(DMSO-d6) δ 1.81-1.87 (m, 2H, CH2), 3.30-3.34 (m, 2H, CH2), 3.52- 3.57 (m, 2H, CH2), 5.75-5.78 (m, 1H, CH), 6.25-6.30 (m, 1H, CH), 6.59-6.66 (m, 1H, CH), 7.19 (t, J=10.48Hz, 1H, pyrimidine-NH), 7.36-7.40 (m, 1H, Ar-H), 7.92-7.97 (m, 4H, Ar-H), 8.11 (s, 1H, pyrimidine-H), 8.34 (d, J=4.6Hz, 1H, Ar-H), 8.73 (t, J=5.44Hz, 1H, NH), 9.95 (s, 1H, phenyl ring- NH), 10.05 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 494 (M+1).
Embodiment 29
The preparation of 3- (4- dimethylamino benzamido) propylcarbamate
White solid 3- (4- dimethylamino benzamido) propylcarbamate (840mg, 91.1% yield) Be by 3- amino propyl aminos t-butyl formate (500mg, 2.87mmol) and 4- dimethylaminobenzoic acids (475mg, 2.87mmol) it is prepared according to the similar step in embodiment 4.LC-MS(m/z)322(M+1).
Embodiment 30
The preparation of N- (3- aminopropyls) -4- dimethylamino benzamides
White solid N- (3- aminopropyls) -4- dimethylamino benzamide (500mg, 86.5% yield) is by 3- (4- Dimethylamino benzamido) propylcarbamate (840mg, 2.62mmol) is according to the similar step in embodiment 5 It is prepared.LC-MS(m/z)222(M+1).
Embodiment 31
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- dimethylamino benzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- dimethylamino benzamide (700mg, 84.3% yield) it is by 2,4,5- trichloropyrimidines (550mg, 3.00mmol) and N- (3- aminopropyls) -4- Dimethylaminobenzene first Amide (500mg, 2.26mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)368(M+1).
Embodiment 32
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- dimethylamino benzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- dimethylamino benzamide (49mg, 58.3% yield) is by N- (3- (2,5- dichloro pyrimidine base -4- amino) Propyl) -4- dimethylamino benzamide (50mg, 0.14mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (30mg, 0.15mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.74-1.78 (m, 2H, CH2), 2.95 (s, 6H, 2 × CH3), 3.25-3.60 (m, 2H, CH2), 3.32 (s, 3H, CH3), 3.41-3.43 (m, 2H, CH2), 5.59 (d, J=9.8Hz, 1H, CH), 6.02-6.09 (m, 1H, CH), 6.16-6.20 (m, 1H, CH), 6.68 (d, J=9.8Hz, 2H, Ar-H), 7.22-7.27 (m, 1H, Ar-H), 7.31-7.34 (m, 1H, Ar-H), 7.64-7.67 (m, 1H, pyrimidine-NH), 7.70 (d, J=8.7Hz, 2H, Ar-H), 7.89-7.90 (m, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.14 (t, J= 5.6Hz, 1H, NH), 9.43 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 526 (M+1).
Embodiment 33
The preparation of 3- (2,4,6- benzamide trifluoroacetate base) propylcarbamate
White solid 3- (2,4,6- benzamide trifluoroacetate base) propylcarbamate (200mg, 60.1% yield) It is by 3- amino propyl aminos t-butyl formate (174mg, 1.0mmol) and 2,4,6- trifluoro-benzoic acids (176mg, 1.0mmol) It is prepared according to the similar step in embodiment 4.LC-MS(m/z)333(M+1).
Embodiment 34
N- (3- aminopropyls) -2, the preparation of 4,6- benzamide trifluoroacetates
White solid N- (3- aminopropyls) -2,4,6- benzamide trifluoroacetates (100mg, 43.1% yield) be by 3- (2, 4,6- benzamide trifluoroacetate bases) propylcarbamate (200mg, 0.6mmol) is according to the similar step system in embodiment 5 It is standby to form.LC-MS(m/z)233(M+1).
Embodiment 35
N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -2, the preparation of 4,6- benzamide trifluoroacetates
Yellow solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -2,4,6- benzamide trifluoroacetates (120mg, 73.6% yield) it is by 2,4,5- trichloropyrimidines (100mg, 0.55mmol) and N- (3- aminopropyls) -2,4,6- trifluoromethyl benzonitriles Amide (100mg, 0.43mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)379(M+1).
Embodiment 36
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 2,4,6- benzamide trifluoroacetates
Yellow solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -2,4,6- benzamide trifluoroacetates (80mg, 58.3% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) Propyl) -2,4,6- benzamide trifluoroacetates (120mg, 0.32mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (110mg, 0.56mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.75-1.82 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.25-3.31 (m, 2H, CH2), 3.44-3.45 (m, 2H, CH2), 5.61 (d, J= 9.5Hz, 1H, CH), 6.04-6.11 (m, 1H, CH), 6.16-6.22 (m, 1H, CH), 7.22-7.28 (m, 4H, Ar-H, pyrimidine- NH), 7.67-7.69 (m, 1H, Ar-H), 7.87 (d, J=5.2Hz, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.71 (t, J =5.4Hz, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 537 (M+1).
Embodiment 37
The preparation of 3- (4- methoxy benzamides base) propylcarbamate
White solid 3- (4- methoxy benzamides base) propylcarbamate (800mg, 90.4% yield) is It is pressed by 3- amino propyl aminos t-butyl formate (500mg, 2.87mmol) and 4- methoxy benzoic acids (437mg, 2.87mmol) It is prepared according to the similar step in embodiment 4.LC-MS(m/z)309(M+1).
Embodiment 38
The preparation of N- (3- aminopropyls) -4- methoxy benzamides
White solid N- (3- aminopropyls) -4- methoxy benzamides (500mg, 92.6% yield) are by 3- (4- first Oxybenzamide base) propylcarbamate (800mg, 2.60mmol) according in embodiment 5 similar step prepare It forms.LC-MS(m/z)209(M+1).
Embodiment 39
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- methoxy benzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- methoxy benzamides (600mg, 70.3% yield) it is by 2,4,5- trichloropyrimidines (690mg, 3.74mmol) and N- (3- aminopropyls) -4- methoxybenzoyls Amine (500mg, 2.40mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)355(M+1).
Embodiment 40
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- methoxy benzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- methoxy benzamides (10mg, 13.9% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) third Base) -4- methoxy benzamides (50mg, 0.14mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (30mg, 0.15mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.77-1.80 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.28-3.31 (m, 2H, CH2), 3.43-3.45 (m, 2H, CH2), 3.80 (s, 3H, CH3), 5.59 (d, J =9.5Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 6.97 (d, J=8.7Hz, 2H, Ar- H), 7.21-7.27 (m, 2H, Ar-H, pyrimidine-NH), 7.65-7.67 (m, 1H, Ar-H), 7.81 (d, J=8.7Hz, 2H, Ar- H), 7.89 (d, J=6.4Hz, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.31 (t, J=5.2Hz, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 513 (M+1).
Embodiment 41
The preparation of 3- (2- cyano nicotinoyl amido) propylcarbamate
White solid 3- (2- cyano nicotinoyl amido) propylcarbamates (400mg, 91.3% yield) are by 3- Amino propyl amino t-butyl formate (250mg, 1.44mmol) and 6- cyano niacin (212mg, 1.44mmol) are according to embodiment 4 In similar step be prepared.LC-MS(m/z)305(M+1).
Embodiment 42
The preparation of N- (3- aminopropyls) -6- cyano niacinamide
White solid N- (3- aminopropyls) -6- cyano niacinamide (240mg, 89.6% yield) is by 3- (2- cyano cigarettes Amide groups) propylcarbamate (400mg, 1.32mmol) is prepared according to the similar step in embodiment 5.LC- MS(m/z)205(M+1)。
Embodiment 43
The preparation of 6- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) niacinamide
White solid 6- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) niacinamide (80mg, 19.3% production Rate) be by 2,4,5- trichloropyrimidines (280mg, 1.53mmol) and N- (3- aminopropyls) -6- cyano niacinamide (240mg, 1.18mmol) it is prepared according to the similar step in embodiment 6.LC-MS(m/z)351(M+1).
Embodiment 44
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 6- cyano niacinamide
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -6- cyano niacinamide (15mg, 17.4% yield) is by 6- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) Propyl) niacinamide (60mg, 0.17mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (46mg, 0.24mmol) It is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.81-1.88 (m, 2H, CH2), 3.21 (s, 3H, CH3), 3.32-3.36 (m, 2H, CH2), 3.46-3.51 (m, 2H, CH2), 5.61 (d, J=9.8Hz, 1H, CH), 6.04-6.1 (m, 1H, CH), 6.17-6.22 (m, 1H, CH), 7.29 (t, J=9.3Hz, 1H, pyrimidine-NH), 7.61-7.62 (m, 1H, Ar- H), 7.78 (s, 1H, Ar-H), 7.83 (d, J=5.3Hz, 1H, Ar-H), 8.06 (s, 1H, pyrimidine-H), 8.17 (d, J= 7.4Hz, 1H, Ar-H), 8.36-8.41 (m, 1H, Ar-H), 8.89 (t, J=5.4Hz, 1H, NH), 9.09 (s, 1H, Ar-H), 9.85 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 509 (M+1).
Embodiment 45
The preparation of 3- (4- (2-hydroxybenzoyl)s amido) propylcarbamate
White solid 3- (4- (2-hydroxybenzoyl)s amido) propylcarbamate (600mg, 71.1% yield) be by 3- amino propyl aminos t-butyl formate (500mg, 2.87mmol) and 4-HBA (440mg, 2.87mmol) are according to reality The similar step applied in example 4 is prepared.LC-MS(m/z)295(M+1).
Embodiment 46
The preparation of N- (3- aminopropyls) -4- hydroxybenzamides
White solid N- (3- aminopropyls) -4- hydroxybenzamides (300mg, 75.8% yield) are by 3- (4- hydroxyls Benzamido) propylcarbamate (600mg, 2.04mmol) is prepared according to the similar step in embodiment 5. LC-MS(m/z)195(M+1)。
Embodiment 47
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- hydroxybenzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- hydroxybenzamides (200mg, 84.3% Yield) be by 2,4,5- trichloropyrimidines (300mg, 1.64mmol) and N- (3- aminopropyls) -4- hydroxybenzamides (300mg, 1.54mmol) it is prepared according to the similar step in embodiment 6.LC-MS(m/z)341(M+1).
Embodiment 48
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- hydroxybenzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- hydroxybenzamides (3mg, 1.3% yield) be by N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) - 4- hydroxybenzamides (200mg, 0.47mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (100mg, 0.52mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.75-1.81 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.27-3.29 (m, 2H, CH2), 3.42-3.44 (m, 2H, CH2), 5.59 (d, J=9.4Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.20 (m, 1H, CH), 6.78 (d, J=7.9Hz, 2H, Ar-H), 7.24-7.27 (m, 2H, Ar-H, pyrimidine-NH), 7.67-7.69 (m, 1H, Ar-H), 7.70 (d, J=8.1Hz, 2H, Ar-H), 7.88-7.90 (m, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.20 (s, 1H, NH), 9.40 (s, 1H, phenyl ring-NH), 9.89 (s, 1H, OH) .LC- MS(m/z)499(M+1)。
Embodiment 49
The preparation of 3- (4- cyano -2- fluorobenzoyls amido) propylcarbamate
White solid 3- (4- cyano -2- fluorobenzoyls amido) propylcarbamate (450mg, 70.1% yield) It is by 3- amino propyl aminos t-butyl formate (348mg, 2.0mmol) and 4- cyano -2- fluobenzoic acids (330mg, 2.0mmol) It is prepared according to the similar step in embodiment 4.LC-MS(m/z)322(M+1).
Embodiment 50
The preparation of N- (3- aminopropyls) -4- cyano -2- fluorobenzamides
White solid N- (3- aminopropyls) -4- cyano -2- fluorobenzamides (278mg, 90.0% yield) are by 3- (4- Cyano -2- fluorobenzoyls amido) propylcarbamate (450mg, 1.4mmol) is according to the similar step in embodiment 5 It is prepared.LC-MS(m/z)222(M+1).
Embodiment 51
The preparation of 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -2- fluorobenzamides
White solid 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -2- fluorobenzamides (312mg, 67.4% yield) it is by 2,4,5- trichloropyrimidines (238mg, 1.3mmol) and N- (3- aminopropyls) -4- cyano -2- fluorobenzene first Amide (278mg, 1.26mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)368(M+1).
Embodiment 52
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- cyano -2- fluorobenzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- cyano -2- fluorobenzamides (106mg, 49.3% yield) are by 4- cyano-N- (3- (2,5- dichloro pyrimidines Base -4- amino) propyl) -2- fluorobenzamides (150mg, 0.41mmol) and N- (5- amino -2- fluorophenyls)-N- metering systems Amide (87mg, 0.45mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6)δ1.80-1.83 (m, 2H, CH2), 3.20 (s, 3H, CH3), 3.30-3.31 (m, 2H, CH2), 3.45-3.47 (m, 2H, CH2), 5.61 (d, J= 9.7Hz, 1H, CH), 6.04-6.10 (m, 1H, CH), 6.15-6.21 (m, 1H, CH), 7.20-7.25 (m, 2H, Ar-H, pyrimidine- NH), 7.62-7.65 (m, 1H, Ar-H), 7.75-7.76 (m, 2H, Ar-H), 7.88-7.94 (m, 2H, Ar-H), 7.96 (s, 1H, Pyrimidine-H), 8.57 (s, 1H, NH), 9.41 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 526 (M+1).
Embodiment 53
The preparation of 3- (4- cyano -3- fluorobenzoyls amido) propylcarbamate
White solid 3- (4- cyano -3- fluorobenzoyls amido) propylcarbamate (462mg, 71.9% yield) It is by 3- amino propyl aminos t-butyl formate (348mg, 2.0mmol) and 4- cyano -3- fluobenzoic acids (330mg, 2.0mmol) It is prepared according to the similar step in embodiment 4.LC-MS(m/z)322(M+1).
Embodiment 54
The preparation of N- (3- aminopropyls) -4- cyano -3- fluorobenzamides
White solid N- (3- aminopropyls) -4- cyano -3- fluorobenzamides (275mg, 86.5% yield) are by 3- (4- Cyano -3- fluorobenzoyls amido) propylcarbamate (462mg, 1.44mmol) is according to the similar step in embodiment 5 It is prepared.LC-MS(m/z)222(M+1).
Embodiment 55
The preparation of 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -3- fluorobenzamides
White solid 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -3- fluorobenzamides (340mg, 74.6% yield) it is by 2,4,5- trichloropyrimidines (229mg, 1.25mmol) and N- (3- aminopropyls) -4- cyano -3- fluorobenzene first Amide (275mg, 1.24mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)368(M+1).
Embodiment 56
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- cyano -3- fluorobenzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- cyano -3- fluorobenzamides (98mg, 45.6% yield) be by 4- cyano-N- (3- (2,5- dichloro pyrimidine bases - 4- amino) propyl) -3- fluorobenzamides (150mg, 0.41mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (87mg, 0.45mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.81-1.84 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.33-3.35 (m, 2H, CH2), 3.45-3.46 (m, 2H, CH2), 5.59 (d, J=9.7Hz, 1H, CH), 6.02-6.09 (m, 1H, CH), 6.21-6.20 (m, 1H, CH), 7.21-7.25 (m, 2H, Ar-H, pyrimidine-NH), 7.63-7.65 (m, 1H, Ar-H), 7.81-7.89 (m, 2H, Ar-H), 7.95 (s, 1H, pyrimidine-H), 8.04-8.12 (m, 2H, Ar-H), 8.76 (t, J=5.6Hz, 1H, NH), 9.45 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 526 (M+1).
Embodiment 57
The preparation of N- (3- (the chloro- 5- methylpyrimidines base -4- amino of 2-) propyl) -4- cyanobenzamides
Yellow solid N- (3- (the chloro- 5- methylpyrimidines base -4- amino of 2-) propyl) -4- cyanobenzamides (100mg, 60.6% yield) it is by 2,4-, bis- chloro- 5- methylpyrimidines (82mg, 0.5mmol) and N- (3- aminopropyls) -4- Cyanophenacyls Amine (100mg, 0.5mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)330(M+1).
Embodiment 58
4- cyano-N- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidine base -4- ammonia Base) propyl)-benzamide preparation
Black solid 4- cyano-N- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidines Base -4- amino) propyl)-benzamide (10mg, 3.3% yield) is by N- (3- (the chloro- 5- methylpyrimidines base -4- amino of 2-) third Base) -4- cyanobenzamides (100mg, 0.61mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (128mg, 0.66mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.82-1.85 (m, 2H, CH2), 1.92 (s, 3H, CH3), 3.19 (s, 3H, CH3), 3.35-3.37 (m, 2H, CH2), 3.43-3.46 (m, 2H, CH2), 5.59 (d, J =9.8Hz, 1H, CH), 6.04-6.1 (m, 1H, CH), 6.15-6.20 (m, 1H, CH), 6.68 (t, J=5.5Hz, 1H, Ar-H), 7.19 (t, J=9.5Hz, 1H, pyrimidine-NH), 7.65-7.67 (m, 2H, Ar-H), 7.93-7.99 (m, 5H, Ar-H, pyrimidine-H), 8.69 (t, J=5.5Hz, 1H, NH), 9.04 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 488 (M+1).
Embodiment 59
The preparation of N- (3- (the chloro- 5-FU base -4- amino of 2-) propyl) 4- cyanobenzamides
Yellow solid N- (3- (the chloro- 5-FU base -4- amino of 2-) propyl) 4- cyanobenzamides (100mg, 60.0% Yield) it is by 2,4-, bis- chloro- 5-FUs (83mg, 0.5mmol) and N- (3- aminopropyls) -4- cyanobenzamides (100mg, 0.5mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)334(M+1).
Embodiment 60
4- cyano-N- (3- (the fluoro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) Propyl) benzamide preparation
Gray solid 4- cyano-N- (3- (the fluoro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidines Base -4- amino) propyl) benzamide (49mg, 58.3% yield) is by N- (3- (the chloro- 5-FU base -4- amino of 2-) third Base) 4- cyanobenzamides (100mg, 0.30mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (110mg, 0.56mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.84-1.85 (m, 2H, CH2), 3.18 (s, 3H, CH3), 3.33-3.35 (m, 2H, CH2), 3.42-3.43 (m, 2H, CH2), 5.59 (d, J=8.6Hz, 1H, CH), 6.02-6.09 (m, 1H, CH), 6.15-6.20 (m, 1H, CH), 7.20 (t, J=9.1Hz, 1H, pyrimidine-NH), 7.47-7.49 (m, 1H, Ar-H), 7.63-7.64 (m, 1H, Ar-H), 7.88-7.89 (m, 2H, Ar-H), 7.92-7.96 (m, 4H, pyrimidine-H, Ar-H), 8.68 (s, 1H, NH), 9.23 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 492 (M+1).
Embodiment 61
The preparation of 3- (2- (4- cyano-phenyls) acetamido) propylcarbamate
White solid 3- (2- (4- cyano-phenyls) acetamido) propylcarbamate (511mg, 80.6% production Rate) be by 3- amino propyl aminos t-butyl formate (348mg, 2.0mmol) and 2- (4- cyano-phenyls) acetic acid (322mg, 2.0mmol) it is prepared according to the similar step in embodiment 4.LC-MS(m/z)318(M+1).
Embodiment 62
The preparation of N- (3- aminopropyls) -2- (4- cyano-phenyls) acetamide
White solid N- (3- aminopropyls) -2- (4- cyano-phenyls) acetamide (312mg, 89.4% yield) is by 3- (2- (4- cyano-phenyls) acetamido) propylcarbamate (511mg, 1.61mmol) is according to similar in embodiment 5 Step is prepared.LC-MS(m/z)218(M+1).
Embodiment 63
The preparation of 2- (4- cyano-phenyls)-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) acetamide
White solid 2- (4- cyano-phenyls)-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) acetamide (360mg, 68.9% yield) it is by 2,4,5- trichloropyrimidines (265mg, 1.45mmol) and N- (3- aminopropyls) -2- (4- cyano-phenyls) Acetamide (312mg, 1.44mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)364(M+1).
Embodiment 64
N- (5- (the chloro- 4- of 5- (3- (2- (4- cyano-phenyls) acetamido) propylcarbamic) pyrimidine radicals -2- amino) -2- fluorine Phenyl)-N methacrylamide preparation
White solid N- (5- (the chloro- 4- of 5- (3- (2- (4- cyano-phenyls) acetamido) propylcarbamic) pyrimidine radicals -2- ammonia Base) -2- fluorophenyls)-N methacrylamide (113mg, 53.1% yield) is by 2- (4- cyano-phenyls)-N- (3- (2,5- bis- Chlorine pyrimidine radicals -4- amino) propyl) acetamide (150mg, 0.41mmol) and N- (5- amino -2- fluorophenyls)-N- methacryls Amine (87mg, 0.45mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.67-1.72 (m, 2H, CH2), 3.08-3.11 (m, 2H, CH2), 3.18 (s, 3H, CH3), 3.37-3.38 (m, 2H, CH2), 3.52 (s, 2H, CH2), 5.60 (d, J=10.2Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 7.19-7.22 (m, 1H, Ar-H), 7.26 (t, J=9.3Hz, 1H, pyrimidine-NH), 7.44 (d, J=8.1Hz, 2H, Ar-H), 7.64-7.66 (m, 1H, Ar- H), 7.74 (d, J=8.2Hz, 2H, Ar-H), 7.88-7.89 (m, 1H, Ar-H), 7.95 (s, 1H, pyrimidine-H), 8.13 (t, J= 5.6Hz, 1H, NH), 9.39 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 522 (M+1).
Embodiment 65
The preparation of 3- (4- cvanobenzenesulfonamides base) propylcarbamate
White solid 3- (4- cyanophenyl sulfonamides base) propylcarbamate (0.25g, 73.7% yield) by It is prepared by following method.4- cyanobenzenesulfonyl chlorides (0.2g, 1.0mmol) and N-Boc-1,3- propane diamine (0.18g, 1.03mmol) are molten It is stirred at room temperature in 5mL THF.Then when addition DIPEA (0.26g, 2.0mmol) room temperature reactions 4 are small.LC-MS tracking is anti- It should.The NaHCO of saturation is poured into after reaction3Aqueous solution in, stirring be precipitated solid.Filtering obtains title intermediate.LC-MS (m/z)340(M+1)。
Embodiment 66
The preparation of N- (3- aminopropyls) -4- cvanobenzenesulfonamides
White solid N- (3- aminopropyls) -4- cvanobenzenesulfonamides (150mg, 85.2% yield) are by 3- (4- cyano Benzene sulfonamido) propylcarbamate (250mg, 0.74mmol) is prepared according to the similar step in embodiment 5. LC-MS(m/z)240(M+1)。
Embodiment 67
The preparation of 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzsulfamide
White solid 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzsulfamide (150mg, 61.9% Yield) be by 2,4,5- trichloropyrimidines (128mg, 0.7mmol) and N- (3- aminopropyls) -4- cvanobenzenesulfonamides (150mg, 0.63mmol) it is prepared according to the similar step in embodiment 6.LC-MS(m/z)386(M+1).
Embodiment 68
N- (5- (the chloro- 4- of 5- (3- (4- cvanobenzenesulfonamides base) propylcarbamic) pyrimidine radicals -2- amino) -2- fluorophenyls) - The preparation of N methacrylamide
White solid N- (5- (the chloro- 4- of 5- (3- (4- cvanobenzenesulfonamides base) propylcarbamic) pyrimidine radicals -2- amino) -2- Fluorophenyl)-N methacrylamide preparation (35mg, 30.7% yield) be by 4- cyano-N- (3- (2,5- dichloro pyrimidine bases- 4- amino) propyl) benzsulfamide (80mg, 0.21mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (43mg, 0.22mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.63-1.70 (m, 2H, CH2), 2.80-2.85 (m, 2H, CH2), 3.17 (s, 3H, CH3), 3.34-3.35 (m, 2H, CH2), 5.60 (d, J=10.3Hz, 1H, CH), 6.02-6.09 (m, 1H, CH), 6.15-6.20 (m, 1H, CH), 7.13-7.16 (m, 1H, Ar-H), 7.25 (t, J= 9.4Hz, 1H, pyrimidine-NH), 7.65-7.67 (m, 1H, Ar-H), 7.81-7.82 (m, 1H, Ar-H), 7.88 (t, J=5.9Hz, 1H, NH), 7.91 (d, J=8.4Hz, 2H, Ar-H), 7.94 (s, 1H, pyrimidine-H), 8.03 (d, J=8.4Hz, 2H, Ar-H), 9.38 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 544 (M+1).
Embodiment 69
The preparation of 4- cyano-N- (3- hydroxypropyls) benzamide
Yellow liquid 4- cyano-N- (3- hydroxypropyls) benzamide (400mg, 99% yield) is by 3- amino -1- third Alcohol (150mg, 2mmol) and 4- cyanobenzoic acids (294mg, 2mmol) are prepared according to the similar step in embodiment 4.LC- MS(m/z)205(M+1)。
Embodiment 70
The preparation of 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- oxygroups) propyl) benzamide
Yellow solid 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- oxygroups) propyl) benzamide (120mg, 17% production Rate) it prepares by the following method.4- cyano-N- (3- hydroxypropyls) benzamides (408mg, 2mmol), which are dissolved in 3mL DMF, to be placed in It is stirred under ice bath, adds in NaH (48mg, 2mmol) after ten minutes, continue to stir, add in 2,4,5- trichloropyrimidines after ten minutes (366mg, 2mmol) removes ice bath, room temperature reaction.LC-MS tracking reactions.200mL brine is poured into after reaction, and yellow is precipitated Dope outwells water layer, adds in 200mLPE ultrasounds, and filtering obtains title intermediate.LC-MS(m/z)351(M+1).
Embodiment 71
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- oxygroups) propyl) - The preparation of 4- cyanobenzamides
Brown solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- oxygen Base) propyl) -4- cyanobenzamides (20mg, 20.0% yield) are by 4- cyano-N- (3- (2,5- dichloro pyrimidine base -4- oxygen Base) propyl) benzamide (70mg, 0.2mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (50mg, 0.24mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.98-2.06 (m, 2H, CH2), 3.18 (s, 3H, CH3), 3.40-3.47 (m, 2H, CH2), 4.45-4.51 (m, 2H, CH2), 5.60 (d, J=9.5Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 7.28 (t, J=9.4Hz, 1H, pyrimidine-NH), 7.64-7.67 (m, 1H, Ar-H), 7.78-7.80 (m, 1H, Ar-H), 7.93 (d, J=8.3Hz, 2H, Ar-H), 7.98 (d, J=8.3Hz, 2H, Ar-H), 8.32 (s, 1H, pyrimidine-H), 8.77 (t, J=5.3Hz, 1H, NH), 9.85 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 509(M+1)。
Embodiment 72
The preparation of 3- (Pyrazinamide base) propylcarbamate
White solid 3- (Pyrazinamide base) propylcarbamate (1.0g, 78.0% yield) is by 3- aminopropans Carbamate (800mg, 4.60mmol) and different nicotinoyl chlorine (900mg, 6.38mmol) are according to similar in embodiment 4 Step is prepared.LC-MS(m/z)280(M+1).
Embodiment 73
The preparation of N- (3- aminopropyls)-Pyrazinamide
White solid N- (3- aminopropyls)-Pyrazinamide (180mg, 28.1% yield) is by 3- (Pyrazinamide base) third Carbamate (1.0g, 3.58mmol) is prepared according to the similar step in embodiment 5.LC-MS(m/z)180 (M+1)。
Embodiment 74
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) Pyrazinamide
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) Pyrazinamide (120mg, 32.8% yield) is By 2,4,5- trichloropyrimidines (276mg, 1.51mmol) and N- (3- aminopropyls)-Pyrazinamides (180mg, 1.00mmol) according to Similar step in embodiment 6 is prepared.LC-MS(m/z)326(M+1).
Embodiment 75
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) is different The preparation of niacinamide
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) Pyrazinamide (4.2mg, 2.3% yield) is by N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) different nicotinoyl Amine (120mg, 0.36mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (70mg, 0.36mmol) are according to implementation Similar step in example 7 is prepared.1H-NMR(DMSO-d6) δ 1.80-1.84 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.26-3.33 (m, 2H, CH2), 3.45-3.47 (m, 2H, CH2), 5.59 (d, J=10.1Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.15-6.20 (m, 1H, CH), 7.23-7.27 (m, 2H, Ar-H, pyrimidine-NH), 7.64-7.66 (m, 1H, Ar-H), 7.72 (d, J=5.6Hz, 2H, Ar-H), 7.89 (d, J=5.2Hz, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 7.70 (d, J =5.5Hz, 2H, Ar-H), 8.73 (s, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 484 (M+1).
Embodiment 76
The preparation of 3- (4- ethylbenzoyls amido) propylcarbamate
White solid 3- (4- ethylbenzoyls amido) propylcarbamate (800mg, 91.1% yield) be by 3- amino propyl aminos t-butyl formate (500mg, 2.87mmol) and 4- ethylamino benzonitriles acyl chlorides (530mg, 3.15mmol) according to Similar step in embodiment 4 is prepared.LC-MS(m/z)307(M+1).
Embodiment 77
The preparation of N- (3- aminopropyls) -4- ethyl benzamides
White solid N- (3- aminopropyls) -4- ethyl benzamides (300mg, 55.7% yield) are by 3- (4- ethyls Benzamido) propylcarbamate (800mg, 2.61mmol) is prepared according to the similar step in embodiment 5. LC-MS(m/z)207(M+1)。
Embodiment 78
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- ethyl benzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- ethyl benzamides (500mg, 97.5% Yield) be by 2,4,5- trichloropyrimidines (300mg, 1.64mmol) and N- (3- aminopropyls) -4- ethyl benzamides (300mg, 1.46mmol) it is prepared according to the similar step in embodiment 6.LC-MS(m/z)353(M+1).
Embodiment 79
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- ethyl benzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- ethyl benzamides (86mg, 59.4% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) third Base) -4- hydroxybenzamides (100mg, 0.28mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (71mg, 0.37mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.19 (t, J=7.6Hz, 3H, CH3), 1.78-1.81 (m, 2H, CH2), 2.62-2.67 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.30-3.33 (m, 2H, CH2), 3.44-3.45 (m, 2H, CH2), 5.59 (d, J=10.1Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 7.22-7.29 (m, 4H, Ar-H, pyrimidine-NH), 7.65-7.67 (m, 1H, Ar-H), 7.76 (m, J=8.0Hz, 2H, Ar-H), 7.89 (d, J=5.2Hz, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.37 (t, J=5.5Hz, 1H, NH), 9.39 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 511 (M+1).
Embodiment 80
The preparation of 3- (4- toluyls amido) propylcarbamate
White solid 3- (4- toluyls amido) propylcarbamate (0.45g, 79% yield) is by 3- Amino propyl amino t-butyl formate (0.3g, 1.95mmol) and 4- methyl benzoyl chlorides (0.34g, 1.95mmol) are according to implementation Similar step in example 76 is prepared.LC-MS(m/z)293(M+1).
Embodiment 81
The preparation of N- (3- aminopropyls) -4- methyl benzamides
White solid N- (3- aminopropyls) -4- methyl benzamides (290mg, 99% yield) are by 3- (4- methylbenzenes Formamido) propylcarbamate (450mg, 1.54mmol) is prepared according to the similar step in embodiment 5. LC-MS(m/z)193(M+1)。
Embodiment 82
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- methyl benzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- methyl benzamides (400mg, 78.1% Yield) be by 2,4,5- trichloropyrimidines (300mg, 1.64mmol) and N- (3- aminopropyls) -4- methyl benzamides (290mg, 1.51mmol) it is prepared according to the similar step in embodiment 6.LC-MS(m/z)339(M+1).
Embodiment 83
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- methyl benzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- methyl benzamides (200mg, 34.2% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) third Base) -4- methyl benzamides (400mg, 1.18mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (400mg, 2.06mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.76-1.83 (m, 2H, CH2), 2.34 (s, 3H, CH3), 3.19 (s, 3H, CH3), 3.29-3.33 (m, 2H, CH2), 3.44-3.45 (m, 2H, CH2), 5.59 (d, J =9.7Hz, 1H, CH), 6.03-6.10 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 7.22-7.26 (m, 4H, Ar-H, it is phonetic Pyridine-NH), 7.65-7.67 (m, 1H, Ar-H), 7.74 (d, J=8.0Hz, 2H, Ar-H), 7.89 (d, J=5.2Hz, 1H, Ar- H), 7.96 (s, 1H, pyrimidine-H), 8.38 (t, J=5.4Hz, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 497 (M+1)。
Embodiment 84
The preparation of 3- benzamido propylcarbamates
White solid 3- benzamidos propylcarbamate (700mg, 88.3% yield) is by 3- aminopropans Carbamate (400mg, 2.85mmol) and chlorobenzoyl chloride (500mg, 3.57mmol) are according to the class in embodiment 76 It is prepared like step.LC-MS(m/z)279(M+1).
Embodiment 85
The preparation of N- (3- aminopropyls) benzamide
White solid N- (3- aminopropyls) benzamide (375mg, 80.4% yield) is by 3- benzamido propyl T-butyl carbamate (700mg, 2.62mmol) is prepared according to the similar step in embodiment 5.LC-MS(m/z)179(M +1)。
Embodiment 86
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzamide
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzamide (556mg, 81.7% yield) is By 2,4,5- trichloropyrimidines (550mg, 3.00mmol) and N- (3- aminopropyls) benzamides (375mg, 2.1mmol) according to reality The similar step applied in example 6 is prepared.LC-MS(m/z)325(M+1).
Embodiment 87
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) benzene The preparation of formamide
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) benzamide (245mg, 42.8% yield) is by N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzoyl Amine (400mg, 1.23mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (280mg, 1.44mmol) are according to reality The similar step applied in example 7 is prepared.1H-NMR(DMSO-d6) δ 1.79-1.83 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.31-3.34 (m, 2H, CH2), 3.44-3.46 (m, 2H, CH2), 5.59 (d, J=9.8Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 7.22-7.27 (m, 2H, Ar-H, pyrimidine-NH), 7.45 (d, J=7.5Hz, 2H, Ar-H), 7.52 (t, J=7.1Hz, 1H, Ar-H), 7.65-7.67 (m, 1H, Ar-H), 7.83 (d, J=5.2Hz, 2H, Ar-H), 7.89 (d, J=7.4Hz, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.46 (t, J=5.2Hz, 1H, NH), 9.40 (s, 1H, phenyl ring- NH).LC-MS(m/z)483(M+1)。
Embodiment 88
The preparation of 3- (3- trifluoromethyl benzamides base) propylcarbamate
White solid 3- (3- trifluoromethyl benzamides base) propylcarbamate (640mg, 79.7% yield) Be by 3- amino propyl aminos t-butyl formate (400mg, 2.32mmol) and 3- trifluoromethyl benzoyl chlorides (596mg, 2.87mmol) it is prepared according to the similar step in embodiment 76.LC-MS(m/z)347(M+1).
Embodiment 89
The preparation of N- (3- aminopropyls) -3- trifluoromethyl benzamides
White solid N- (3- aminopropyls) -3- trifluoromethyl benzamides (300mg, 66.0% yield) are by 3- (3- Trifluoromethyl benzamide base) propylcarbamate (640mg, 1.84mmol) is according to the similar step in embodiment 5 It is prepared.LC-MS(m/z)247(M+1).
Embodiment 90
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -3- trifluoromethyl benzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -3- trifluoromethyl benzamides (480mg, 93.2% yield) it is by 2,4,5- trichloropyrimidines (360mg, 2.21mmol) and N- (3- aminopropyls) -3- trifluoromethylbenzene first Amide (300mg, 1.47mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)393(M+1).
Embodiment 91
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 3- trifluoromethyl benzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -3- trifluoromethyl benzamides (240mg, 35.7% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) Propyl) -3- trifluoromethyl benzamides (480mg, 1.22mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (260mg, 1.34mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.80-1.87 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.32-3.37 (m, 2H, CH2), 3.44-3.48 (m, 2H, CH2), 5.59 (d, J= 9.6Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 7.21-7.25 (m, 2H, Ar-H, pyrimidine- NH), 7.65-7.67 (m, 1H, Ar-H), 7.71 (t, J=7.8Hz, 1H, Ar-H), 7.88-7.90 (m, 2H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.14 (d, J=7.9Hz, 1H, Ar-H), 8.16 (s, 1H, Ar-H), 8.72 (t, J=5.4Hz, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 551 (M+1).
Embodiment 92
The preparation of 3- (3- Cyanophenacyls amido) propylcarbamate
White solid 3- (3- Cyanophenacyls amido) propylcarbamate (740mg, 80.6% yield) be by 3- amino propyl aminos t-butyl formate (600mg, 3.44mmol) and 3- cyano-benzoyl chlorides (500mg, 3.02mmol) according to Similar step in embodiment 76 is prepared.LC-MS(m/z)304(M+1).
Embodiment 93
The preparation of N- (3- aminopropyls) -3- cyanobenzamides
White solid N- (3- aminopropyls) -3- cyanobenzamides (300mg, 86.5% yield) are by 3- (3- cyano Benzamido) propylcarbamate (740mg, 2.62mmol) is prepared according to the similar step in embodiment 5. LC-MS(m/z)204(M+1)。
Embodiment 94
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -3- cyanobenzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -3- cyanobenzamides (460mg, 89.4% Yield) be by 2,4,5- trichloropyrimidines (360mg, 2.21mmol) and N- (3- aminopropyls) -3- cyanobenzamides (300mg, 1.47mmol) it is prepared according to the similar step in embodiment 6.LC-MS(m/z)350(M+1).
Embodiment 95
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 3- cyanobenzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -3- cyanobenzamides (210mg, 31.8% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) third Base) -3- cyanobenzamides (460mg, 1.31mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (280mg, 1.44mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.80-1.86 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.31-3.35 (m, 2H, CH2), 3.44-3.48 (m, 2H, CH2), 5.59 (d, J=10.2Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 7.21-7.26 (m, 2H, Ar-H, pyrimidine-NH), 7.64- 7.66 (m, 1H, Ar-H), 7.68-7.70 (m, 1H, Ar-H), 7.89-7.90 (m, 1H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 7.98 (d, J=7.7Hz, 1H, Ar-H), 8.13 (d, J=7.9Hz, 1H, Ar-H), 8.24 (s, 1H, Ar-H), 8.66 (t, J= 5.7Hz, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 508 (M+1).
Embodiment 100
The preparation of 3- (the fluoro- 4- trifluoromethyl benzamides bases of 3-) propylcarbamate
Yellow solid 3- (the fluoro- 4- trifluoromethyl benzamides bases of 3-) propylcarbamate (728mg, 100% production Rate) be by 3- amino propyl aminos t-butyl formate (348mg, 2mmol) and the fluoro- 4- trifluoromethylbenzoic acids of 3- (416mg, 2mmol) it is prepared according to the similar step in embodiment 4.LC-MS(m/z)365(M+1).
Embodiment 101
The preparation of the fluoro- 4- trifluoromethyl benzamides of N- (3- aminopropyls) -3-
The fluoro- 4- trifluoromethyl benzamides of white solid N- (3- aminopropyls) -3- (264mg, 50% yield) are by 3- (the fluoro- 4- trifluoromethyl benzamides bases of 3-) propylcarbamate (728mg, 2mmol) is according to similar in embodiment 5 Step is prepared.LC-MS(m/z)265(M+1).
Embodiment 102
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) fluoro- 4- trifluoromethyl benzamides of -3-
Yellow solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) fluoro- 4- trifluoromethyl benzamides of -3- (200mg, 49% yield) is by 2,4,5- trichloropyrimidines (183mg, 1.00mmol) and the fluoro- 4- tri- of N- (3- aminopropyls) -3- Methyl fluoride benzamide (264mg, 1.00mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)411(M +1)。
Embodiment 103
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of the fluoro- 4- trifluoromethyl benzamides of 3-
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) the fluoro- 4- trifluoromethyl benzamides of -3- (50mg, 20% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- ammonia Base) propyl) the fluoro- 4- trifluoromethyl benzamides (205mg, 0.5mmol) of -3- and N- (5- amino -2- fluorophenyls)-N- methyl-props Acrylamide (110mg, 0.6mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6)δ1.81-1.86 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.32-3.36 (m, 2H, CH2), 3.45-3.47 (m, 2H, CH2), 5.59 (d, J= 9.4Hz, 1H, CH), 6.02-6.09 (m, 1H, CH), 6.15-6.20 (m, 1H, CH), 7.20-7.24 (m, 2H, Ar-H, pyrimidine- NH), 7.64-7.66 (m, 1H, Ar-H), 7.83-7.92 (m, 4H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.75 (t, J= 5.2Hz, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 569 (M+1).
Embodiment 104
The preparation of 3- (2,3,4,5- tetrafluorobenzamide base) propylcarbamate
White solid 3- (2,3,4,5- tetrafluorobenzamide base) propylcarbamate (400mg, 57.1% production Rate) be by 3- amino propyl aminos t-butyl formate (348mg, 2.00mmol) and 2,3,4,5- phenyl tetrafluoride formyl chlorides (848mg, 4.00mmol) it is prepared according to the similar step in embodiment 76.LC-MS(m/z)351(M+1).
Embodiment 105
N- (3- aminopropyls) -2, the preparation of 3,4,5- tetrafluorobenzamides
White solid N- (3- aminopropyls) -2,3,4,5- tetrafluorobenzamides (250mg, 100% yield) be by 3- (2, 3,4,5- tetrafluorobenzamide bases) propylcarbamate (350mg, 1.00mmol) is according to the similar step in embodiment 5 Suddenly it is prepared.LC-MS(m/z)251(M+1).
Embodiment 106
N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -2, the preparation of 3,4,5- tetrafluorobenzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -2,3,4,5- tetrafluorobenzamides (200mg, 50% yield) it is by -2,3,4,5- phenyl tetrafluoride first of 2,4,5- trichloropyrimidines (183mg, 1.00mmol) and N- (3- aminopropyls) Amide (250mg, 1.00mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)397(M+1).
Embodiment 107
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 2,3,4,5- tetrafluorobenzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -2,3,4,5- tetrafluorobenzamides (50mg, 18% yield) are by N- (3- (2,5- dichloro pyrimidine base -4- amino) Propyl) -2,3,4,5- tetrafluorobenzamides (200mg, 0.5mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (110mg, 0.6mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.79-1.82 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.28-3.30 (m, 2H, CH2), 3.44-3.46 (m, 2H, CH2), 5.60 (d, J=9.8Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.21 (m, 1H, CH), 7.23-7.27 (m, 2H, Ar-H, pyrimidine-NH), 7.56-7.61 (m, 1H, Ar-H), 7.65-7.67 (m, 1H, Ar-H), 7.88 (d, J=5.4Hz, 1H, Ar-H), 7.95 (s, 1H, Pyrimidine-H), 8.52 (s, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 555 (M+1).
Embodiment 108
The preparation of 3- (4- acetylbenzenes formamido) propylcarbamate
White solid 3- (4- acetylbenzenes formamido) propylcarbamate (385mg, 60.2% yield) is It is pressed by 3- amino propyl aminos t-butyl formate (350mg, 2.01mmol) and 4- acetylbenzoic acids (328mg, 2.00mmol) It is prepared according to the similar step in embodiment 4.LC-MS(m/z)321(M+1).
Embodiment 109
The preparation of 4- acetyl group-N- (3- aminopropyls) benzamide
White solid 4- acetyl group-N- (3- aminopropyls) benzamide (200mg, 75.8% yield) is by 3- (4- second Acyl group benzamido) propylcarbamate (385mg, 1.20mmol) according in embodiment 5 similar step prepare It forms.LC-MS(m/z)221(M+1).
Embodiment 110
The preparation of 4- acetyl group-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzamide
White solid 4- acetyl group-N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) benzamide (120mg, 36.1% yield) it is by 2,4,5- trichloropyrimidines (180mg, 0.98mmol) and 4- acetyl group-N- (3- aminopropyls) benzoyl Amine (200mg, 0.91mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)367(M+1).
Embodiment 111
4- acetyl group-N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) benzamide preparation
White solid 4- acetyl group-N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidines Base -4- amino) propyl) benzamide (83mg, 47.9% yield) is by 4- acetyl group-N- (3- (2,5- dichloro pyrimidine base -4- Amino) propyl) benzamide (120mg, 0.33mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (70mg, 0.36mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.79-1.85 (m, 2H, CH2), 2.61 (s, 3H, CH3), 3.19 (s, 3H, CH3), 3.32-3.36 (m, 2H, CH2), 3.45-3.48 (m, 2H, CH2), 5.59 (d, J =9.9Hz, 1H, CH), 6.02-6.09 (m, 1H, CH), 6.15-6.20 (m, 1H, CH), 7.21-7.28 (m, 2H, pyrimidine-NH, Ar-H), 7.64-7.69 (m, 1H, Ar-H), 7.88-7.89 (m, 1H, Ar-H), 7.94 (d, J=8.3Hz, 2H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.01 (d, J=8.4Hz, 2H, Ar-H), 8.65 (t, J=5.3Hz, 1H, NH), 9.40 (s, 1H, phenyl ring- NH).LC-MS(m/z)525(M+1)。
Embodiment 112
The preparation of 3- (4- difluoromethyls benzamido) propylcarbamate
White solid 3- (4- difluoromethyls benzamido) propylcarbamate (780mg, 84.3% yield) Be by 3- amino propyl aminos t-butyl formate (490mg, 2.82mmol) and 4- difluoromethyls benzoic acid (485mg, 2.82mmol) it is prepared according to the similar step in embodiment 4.LC-MS(m/z)329(M+1).
Embodiment 113
The preparation of N- (3- aminopropyls) -4- difluoromethyl benzamides
White solid N- (3- aminopropyls) -4- difluoromethyls benzamide (180mg, 33.2% yield) is by 3- (4- Difluoromethyl benzamido) propylcarbamate (780mg, 2.38mmol) is according to the similar step in embodiment 5 It is prepared.LC-MS(m/z)229(M+1).
Embodiment 114
The preparation of N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- difluoromethyl benzamides
White solid N- (3- (2,5- dichloro pyrimidine base -4- amino) propyl) -4- difluoromethyls benzamide (250mg, 84.5% yield) it is by 2,4,5- trichloropyrimidines (180mg, 0.98mmol) and N- (3- aminopropyls) -4- benzal fluoride first Amide (180mg, 0.79mmol) is prepared according to the similar step in embodiment 6.LC-MS(m/z)375(M+1).
Embodiment 115
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) - The preparation of 4- difluoromethyl benzamides
White solid N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) propyl) -4- difluoromethyls benzamide (26mg, 23.2% yield) is by N- (3- (2,5- dichloro pyrimidine base -4- amino) Propyl) -4- difluoromethyls benzamide (80mg, 0.21mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (50mg, 0.26mmol) is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.81-1.84 (m, 2H, CH2), 3.19 (s, 3H, CH3), 3.32-3.40 (m, 2H, CH2), 3.45-3.47 (m, 2H, CH2), 5.59 (d, J=9.4Hz, 1H, CH), 6.03-6.09 (m, 1H, CH), 6.16-6.20 (m, 1H, CH), 6.94 (s, 0.4H, CHF2), 7.08 (s, 0.6H, CHF2), 7.22-7.26 (m, 2H, Ar-H, pyrimidine-NH), 7.64-7.66 (m, 3H, Ar-H), 7.89-7.90 (m, 1H, Ar-H), 7.95 (d, J=7.3Hz, 2H, Ar-H), 7.96 (s, 1H, pyrimidine-H), 8.59 (s, 1H, NH), 9.40 (s, 1H, phenyl ring-NH) .LC-MS(m/z)533(M+1)。
Embodiment 120
The preparation of 6- (4- Cyanophenacyls amido) hexylamino t-butyl formate
White solid 6- (4- Cyanophenacyls amido) hexylamino t-butyl formate (1300mg, 73.4% yield) be by 6- hexylaminos t-butyl formate (1100mg, 5.09mmol) and 4- cyano-benzoyl chlorides (900mg, 5.45mmol) are according to implementation Similar step in example 76 is prepared.LC-MS(m/z)346(M+1).
Embodiment 121
The preparation of N- (6- Aminohexyls) -4- cyanobenzamides
White solid N- (6- Aminohexyls) -4- cyanobenzamides (700mg, 75.6% yield) are by 6- (4- cyano Benzamido) hexylamino t-butyl formate (1300mg, 3.76mmol) according in embodiment 5 similar step prepare and Into.LC-MS(m/z)246(M+1).
Embodiment 122
The preparation of 4- cyano-N- (6- (2,5- dichloro pyrimidine base -4- amino) hexyl) benzamide
White solid 4- cyano-N- (6- (2,5- dichloro pyrimidine base -4- amino) hexyl) benzamide (80mg, 49.7% Yield) be by 2,4,5- trichloropyrimidines (120mg, 0.66mmol) and N- (6- Aminohexyls) -4- cyanobenzamides (100mg, 0.41mmol) it is prepared according to the similar step in embodiment 6.LC-MS(m/z)392(M+1).
Embodiment 123
N- (6- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) hexyl) - The preparation of 4- cyanobenzamides
White solid N- (6- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- ammonia Base) hexyl) -4- cyanobenzamides (47mg, 50.3% yield) are by 4- cyano-N- (6- (2,5- dichloro pyrimidine base -4- ammonia Base) hexyl) benzamide (68mg, 0.17mmol) and N- (5- amino -2- fluorophenyls)-N methacrylamide (46mg, 0.24mmol) it is prepared according to the similar step in embodiment 7.1H-NMR(DMSO-d6) δ 1.30-1.32 (m, 4H, 2 × CH2), 1.52-1.56 (m, 4H, 2 × CH2), 3.19 (s, 3H, CH3), 3.26-3.29 (m, 2H, CH2), 3.36-3.37 (m, 2H, CH2), 5.60 (d, J=9.9Hz, 1H, CH), 6.03-6.10 (m, 1H, CH), 6.17-6.21 (m, 1H, CH), 7.22-7.27 (m, 2H, pyrimidine-NH, Ar-H), 7.59-7.61 (m, 1H, Ar-H), 7.93-7.98 (m, 6H, pyrimidine-NH, Ar-H), 8.64 (s, 1H, NH), 9.38 (s, 1H, phenyl ring-NH) .LC-MS (m/z) 550 (M+1).
Extracorporeal biology is evaluated
This detection method is evaluated for the external activity of compound of the present invention, including external zymetology activity rating side Method, cells growth activity evaluation method and intracellular reactive evaluation method.
The purpose of this detection is body of the overall merit difference compound to kinases such as JAK, ITK, BLK, TBK1 and VEGFR Outer zymetology inhibitory activity feature, subtype-selective feature and the biological activity influence on cell model, including cell growth Activity and signal path adjust activity.
Embodiment A the enzyme activities detect
Test cardinal principle
The basic principle of external zymetology Activity determination is the specific substrate using fluorescent marker, is carried out under zymogenesis Phosphorylation, phosphorylated substrate and phosphorylated substrate different wave length can generate fluorescence signal of different strengths and weaknesses (445nm with 520nm).When adding in different test compounds, the degree of substrate phosphorylation is presented as to the inhibition of kinase activity, so as to table Reveal different fluorescence signals, and inhibitory activity of the compound to kinases is calculated with this.Basic testing principle such as 1 institute of attached drawing Show.
The detection of zymetology inhibitory activity using the people of GST marks recombinate JAKs kinases JAK1/PV4774, JAK2/PV4210, JAK3/PV3855, TYK2/PV4790 and its corresponding specific substrate Tyr6 (Z '-Kinase Assay Kit- Tyrosine6Peptide, JAK1/PV4122), Tyr4 (Z '-Kinase Assay Kit- Tyrosine4Peptide, JAK2/PV3193), Tyr4 (Z '-Kinase Assay Kit- Tyrosine4Peptide, JAK3/PV3193), Tyr3 (Z '-Kinase Assay Kit- Tyrosine4Peptide, TYK2/PV3192).Detection reagent be color developing agent A (Development reagent A, PV3297).Above-mentioned all material is bought from Invitrogen companies.
Test main process
The flow that experimentation is required according to detection reagent operation instructions carries out (Invitrogen).Flow is as follows：
(1) Preparatory work of experiment：Kinase reaction buffer solution (working solution) is prepared as requested, will be tested with kinase reaction buffer solution Diluted chemical compound (detects JAK1, JAK2, TYK2, compound maximum concentration is 10 μM into various concentration gradient；JAK3 is examined It surveys, compound maximum concentration is 1 μM).
(2) 10 μ L of zymetology reaction system, it is molten comprising 2.5 μ L tests compound, 5 μ L kinase reactions buffer solutions and 2.5 μ LATP Liquid (kit offer), after mixing, when room temperature reaction 1 is small.
(3) detection reaction is provided with control reaction simultaneously, including being not added with the solvent control of test compound, being not added with The negative control of ATP and the positive control for adding phosphorylated substrate.All detections are repeated 3 times.
(4) zymetology after reaction, adds in the chromogenic reaction buffer solution that 5 μ L are prepared in advance, when room temperature reaction 1 is small.Then It adds in 5 μ L stop buffers and terminates reaction.
(5) detected using fluorescence detector (Ascent Fluoroskan FL reader, Thermo Labsystems) Fluorescence signal per hole, excitation wavelength 400nm, the launch wavelength of detection is respectively 445nm and 520nm.Substrate phosphorylation Ratio is with reference to fluorescence signal intensity C445/F520.
(6) the zymetology inhibiting rate calculation formula of compound is tested：Inhibiting rate (%)=1- detection holes substrate phosphorylation/solvent Control wells phosphoric acid rate.IC is utilized after calculating inhibition of phosphorylation rate respectively to the test compound of various concentration gradient50It calculates Device calculates zymetology 503nhibiting concentration (IC50)。
According to above-mentioned experimental method, with Xeljanz (citric acid tropsch imatinib) for positive reference compound, by institute of the present invention The external JAKs zymetologys evaluation of compound progress is stated (to detect JAK3 and JAK2, test compound concentration is 30nM；JAK1 is examined It surveys, test compound concentration is 300nM).Data brief summary see the table below (table 2).
2 representative compound of the present invention of table inhibits the zymetology data of JAKs
aRV=tests the inhibiting rate ratio of compound/Xeljanz；ND (does not have data)
Upper table statistics indicate that：Compared with positive control drug, the compounds of this invention has selective JAK 3 and/or JAK1 kinases Inhibitory activity.
Select part of compounds commission Eurofins company (http of the present invention：//www.eurofins.com) it carries out Kinases spectrum screening (KinaseProfilerTM) and zymetology inhibitory activity (IC50ProfilerTM) measure.Complete swashing for screening active ingredients In enzyme in addition to JAK family kinases, further include 4 kinases of most Group 3F and Group (ITK, BLK, TBK1, VEGFRs, ERBBs etc.) and hematological system associated kinase (Zhang J., et al.2009, Nat.Rev.Cancer., 9：28-39).It surveys It is 1 μM to try compound and carry out the concentration that kinases spectrum is screened, IC50It measures using 9 semilog concentration gradients.Experiment detection according to The standard test flow of Eurofins companies is carried out.Experimental method is as follows：It is required according to the reaction of different kinases, 0.2 μ L tests Compound (50 μM are dissolved in dimethyl sulfoxide (DMSO) DMSO) add in containing specific kinases reaction buffer (it is different according to kinases type, Buffer system includes respectively：20mM MOPS, 1mM EDTA, 0.01%Brij-35,5%Glycerol, 0.1% β- Mercaptoethanol, 1mg/mL BSA or 50mM TRIS, 0.1mM EGTA, 0.1mM Na3VO4,0.1% β-sulfydryl second Alcohol, 1mg/mL BSA), then sequentially add final concentration of 50 μM kinases specific substrate (different kinases use different bottoms Object), the γ of 10mM MgAcetate and isotope marks-33P ATP (radioactivity about 500cpm/pmol), reaction system are overall Product is 10 μ L.Incubation at room temperature 40 minutes is terminated with 3% phosphoric acid and reacted, then continues at filter net type low temperature spray drying equipment (P30filtermat), cleaned once with methanol three times with the cleaning of 75mM phosphoric acid, radioactivity detection is carried out after dry.Specific behaviour Make the Standard Operating Procedure that flow is provided referring to Eurofins companies：http：//www.eurofins.com/media/ 9724077/kinaseprofiler_assav_protocol_guide_eurofi ns_v64.pdf).Data brief summary see the table below (table 3).
3 representative compound of the present invention of table inhibits the IC of JAKs, ITK, BLK, TBK1 and VEGFR50(nM)
ND (does not have data)
Upper table statistics indicate that：(1) part of compounds of the present invention has selective JAK 3 and/or JAK1 kinase inhibiting activities. (2) part of compounds of the present invention has inhibitory activity to the part kinases in ITK, BLK, TBK1 and VEGFR family.
Embodiment B cells growth activities detect
As previously mentioned, the distribution of JAKs kinase expressions has Specific Distribution, in addition to immune system cell, in other cells Type also has expression.JAK3 is mainly expressed in T lymphocytes, and the distribution of other hypotypes is relatively broad.Jak kinase is by mediating not Same cytokine signaling has potential influence to the growth activity of target cell.JAKs kinase inhibitors are by inhibiting different Asias The JAKs of type, so as to the growth to model cell, there may be different effects.
MTS is detected as regular growth virus detection method, and basic principle is that the dehydrogenase in living cells mitochondria being capable of generation Thank to the new type first Za compound MTS of reduction yellow as formazan, the first Za product that 490nm absorption values (OD) measure amount directly with The quantity of living cells is directly proportional in culture, therefore the number of living cells can be deduced according to OD values, understands test compound suppression Cell growth processed or the ability for killing cell.
This experimental basis MTS detection methods evaluate compound on intracellular of the present invention using different types of cell model The influence of growth activity, and then understand its intracellular activation characteristics.
(1) CTLL-2 cell models
Test cardinal principle
JAKs activity has a significant effect to the growth of immunocyte.For the T lymphocytes of activation and proliferation, its growth relies on JAK1,3 kinase activities in growth factor acceptor IL-2 and downstream.
This experiment uses mouse T lymphocyte system CTLL-2, and the multiplication growth of the cell line depends critically upon IL-2, usually For evaluating the active potency of external source IL-2.By inhibiting JAK1/3 kinase activities, can inhibit under condition of culture in vitro CTLL-2 cell Proliferations.T lymphocyte activations multiplication is also the important pathological characters of various immunity diseases.Therefore, this model There is Correlation with Pathology simultaneously.
Using MTS detection methods, the variation of absorbance is generated by comparing cell after the processing of compound after tested, is come Solution tests growth inhibitory activity of the compound to model cell, and then evaluates compound and live to the potential inhibition of JAK1/3 accesses Property.
Test main process
MTS routinely experimental implementation flows, test and are carried out in 96 orifice plates.
Model cell is inoculated into according to appropriate concentration (about 20,000/per hole) in 96 well culture plates, 24 it is small when after plus Enter the test compound (10 μM of highest final concentration) of various concentration gradient, while solvent control (DMSO) and negative control are set Hole is set according to 3 repeating holes.Cell continue culture 24 it is small when after be detected.
CTLL-2 is suspension cell, and after culture, MTS and PMS that 20 μ L are prepared in advance are directly added in into culture hole Mixed liquor (according to 20: 1 ratio mix), when 37 DEG C of incubator cultures 2 are small after be detected (490nm) with microplate reader.
After the background value for deducting negative control, test the influence of compounds on cell growth, by comparing instrument connection and The OD value differences in solvent control hole are different to be calculated.Life to model cell is calculated the test compound of various concentration gradient respectively Long rate, and calculate its growth 503nhibiting concentration (GI50)。
(2) HeLa and HUVEC cell models
Test cardinal principle
HeLa cells are Human cervical cancer cell lines, belong to epithelial types tumor cell line；HUVEC is in human umbilical vein Chrotoplast belongs to endothelium in type primary cell；Both cells express other hypotypes in addition to JAK3.
Jak kinase activity change has not significant impact the growth of other cell types in addition to immunocyte, in utilization Two kinds of cell model primary evaluation test compounds are stated with the presence or absence of other kinases target spots that cell growth is influenced beyond jak kinase Or non-selective cytotoxicity.
Experiment after being incubated specified time altogether with the test compound of various concentration, utilizes MTS using the cell model of culture The influence of method detection test compound processing cell growth.
Test main process
MTS routinely experimental implementation flows, test and are carried out in 96 orifice plates.
Model cell is inoculated into according to appropriate concentration (about 5000/per hole) in 96 well culture plates, 24 it is small when after add in The test compound (40 μM of highest final concentration) of various concentration gradient, while solvent control (DMSO) and negative control hole are set, It is set according to 3 repeating holes.Cell continue culture 72 it is small when after be detected.
Suction out all culture solutions in culture hole, added in per hole MTS that 100 μ L fresh cultures and 20 μ L prepare in advance and PMS mixed liquors (according to 20: 1 ratio mix), when 37 DEG C of incubator cultures 2 are small after be detected (490nm) with microplate reader.
Test the cell growth rate and GI of compound50Computational methods be same as above.
According to above-mentioned experimental method, compound of the present invention is subjected to cytology evaluation and (to CTLL-2 cell detections, is surveyed Examination compound concentration is 300nM；To HeLa and HUVEC cell detections, test compound concentration is 10 μM).Data brief summary is seen below Table (table 4).
Growth rate of 4 representative compound of the present invention of table in different cell lines
ND (does not have data)
Upper table statistics indicate that：Part of compounds of the present invention has the CTLL-2 cell inhibitory activities of specificity.
According to cytologic experiment method, using Xeljanz as positive reference compound, the compounds of this invention is selected to carry out external The IC of JAKs zymetologys50With the GI to different cell lines50It measures.As a result see the table below (table 5).
GI of 5 representative compound of the present invention of table in different cell lines50(μM)
ND (does not have data)
Upper table statistics indicate that：Compared with positive control drug, the compounds of this invention has highly selective JAK3 kinase inhibitions Activity, while these compounds also have the cell inhibitory activity of good specific CTL L-2.
Embodiment C intracellular reactives are evaluated
Cell factor, jak kinase and stat protein signal path are a complicated network systems, different cell factors The heterodimer formed by activating specific JAK hypotypes homodimer or different subtype, and then promote different STAT eggs The phosphorylation of white member.On different cell models, stimulated, can detected and related JAK using specific cell factor The specifically relevant downstream STAT phosphorylation signals of hypotype, and JAK inhibitor inhibits this by inhibiting the activity of associated kinase Pathway activity, it is possible thereby to intracellular inhibitory activity of the evaluation test compound to different JAK hypotypes.
This experiment uses protein immunoblot (WB) method and flow cytometry, utilizes U937, THP-1, CTLL-2, UT- 7/EPO and the human peripheral blood cell of activation (hPBC) totally 5 kinds of cell models, are examined by comparing STATs phosphorylations and non-phosphorylating Survey the intracellular reactive of the relative level evaluation testing compound of signal.In this experiment the WB primary antibodies that use of hybridization and secondary antibody from Cell Signaling company (http：//www.cellsignal.com) it buys, the fluorescent marker that flow cytometry uses resists Body is from eBiosciences companies (http：//www.ebioscience.com) purchase.
Test cardinal principle
U937 is monocytic series, and cell factor IFN γ causes downstream by activating JAK1/2 heterodimers STAT5a phosphorylations inhibit STAT5a phosphorylations by inhibiting JAK1/2 activity.Based on this, by detecting STAT5 phosphoric acid Changing horizontal variation can be with evaluation test compound to the intracellular inhibitory activity of JAK1/2.
THP-1 is monocytic series, and cell factor IL-4 causes downstream STAT6 by activating JAK1/3 heterodimers Phosphorylation, JAK inhibitor compounds inhibit STAT6 phosphorylations by inhibiting JAK1/3 activity.By detecting STAT6 phosphoric acid The horizontal variation of change can evaluate intracellular inhibitory activity of the compound to JAK1/3.
CTLL-2 is T lymphocytic series, and multiplication growth passes through activation dependent on cell factor IL-2, cell factor IL-2 JAK1/3 heterodimers, cause downstream STAT5 phosphorylations, and JAK inhibitor compounds are pressed down by inhibiting JAK1/3 activity STAT5 phosphorylations processed.Intracellular inhibition work of the compound to JAK1/3 can be evaluated by detecting the variation of STAT5 phosphorylation levels Property.
UT-7/EPO is the cell line formed from giant cell leukaemic marrow after EPO Fiber differentiations, to thin Intracellular cytokine EPO has significant reaction, and EPO signals are transferred via JAK2 homodimers, causes downstream STAT5 phosphorylations, JAK suppressions Inhibitor compound inhibits STAT5 phosphorylations by inhibiting JAK2 activity.It can be with by detecting the variation of STAT5 phosphorylation levels Evaluate intracellular inhibitory activity of the compound to JAK2.
Human peripheral blood cell (hPBC) forms the multiplication that cell factor IL-2 is relied on after CD3 antibody costimulation activation, The growth signals access is mediated by JAK1/3 heterodimers, and causes downstream STAT5 phosphorylations.By detecting STAT5 phosphoric acid The horizontal variation of change can evaluate intracellular inhibitory activity of the compound to JAK1/3.
Test main process
Protein immunoblot (WB)
(1) compound is handled：Using 6 orifice plates, U937, THP-1 cell are cultivated respectively to suitable density for experiment, are added in different The test compound of concentration is incubated overnight when small (16), adds in corresponding IFN γ, IL-4 (10ng/mL), centrifuged after 30 minutes Collect corresponding cell.
(2) protein extraction and WB detections：Quantitative after protein extraction, albumen transferring film after PAGE electrophoresis, WB is detected according to mark Quasi-experiment flow carries out.Hybridize the secondary antibody used includes STAT5 (#9363), STAT6 (#9362) and corresponding phosphorylation respectively STAT5 (#9351), STAT6 (#9361) are detected according to the method that antibody specification is recommended.
(3) signal detection：Hybridization signal detection is imaged using X-ray, and the grey scale signal after scanning is converted into digital signal, The relative signal intensity of phosphorylation STATs and STATs are calculated respectively, and then are evaluated compound and lived to the inhibition of phosphorylation of STATs Property.
Flow cytometry (FCS)
(1) compound is handled：Experiment uses the volunteer of 6 orifice plates, THP-1, CTLL-2, UT7/EPO and Activated in Vitro Peripheral blood cells (hPBC) are cultivated respectively to suitable density, add in the test compound of various concentration, are incubated overnight when small (16), Corresponding IFN γ, IL-4, IL-2, EPO (10ng/mL) are added in, corresponding cell is collected by centrifugation after 30 minutes.
(2) cell is fixed and fluorescent marker：Cell fixes (30 minutes) using paraformaldehyde, is then carried out with refrigerated methanol Permeable membrane handles (15 minutes).Suspension is made after being cleaned with PBS buffer solution in cell, and anti-phosphorylation is added according to 100: 1 ratio STAT5, STAT6 antibody (Mouse anti-Human p-STAT5 (pY694)-；Mouse anti-Rabbit p-STAT6(pY641)-), incubation 30 minutes is protected from light, loading suspension to be made after PBS cleaning.
(3) FCM analysis：Detection usesEasyCyte flow cytometers are carried out according to instrument specification Detection operation selectes the median fluorescent signal (MFI) of suitable cell mass measurement sample, on this basis, with reference in experiment Negative (not plus the factor stimulates) and the signal of positive control (adding factor stimulation and solvent control) sample, calculates different chemical combination respectively The relative signal intensity of phosphorylation STATs under object concentration for the treatment of, and then calculate evaluation compound and live to STATs inhibition of phosphorylation The IC of property50Value.
According to above-mentioned experimental method, the compounds of this invention is selected to carry out WB and FCM analysis, which part compound To the STATs inhibition of phosphorylation IC in specific cells model50Value.Data brief summary see the table below (table 6).
The inhibition of phosphorylation data of 6 the compounds of this invention of table
ND (does not have data)
Upper table statistics indicate that：Part of compounds of the present invention has JAK3 the and/or JAK1 inhibitory activity of intracellular selectivity, It is consistent with external zymetology evaluation result.
Influence in arthritis (CIA) model that embodiment D test compounds are induced in anti-rat collagen albumen
Purpose：This experiment induces Wistar rat arthritis with chicken Collagen Type VI, gives embodiment 7 and embodiment 22 in vivo Compound makees the treatment of rat arthritis come evaluation test compound by observing the variation of rat arthritis disease index With.
Experimental animal：36 female Wistar rats, when beginning one's study, weight 180-200g is purchased from Guangzhou Zhongshan University and moves Object experimental center.Four groups (every group 8) are used for arthritis model, separately have one group (4) to be used as normal control.
Experiment material：Chicken II collagen types, Freund's complete adjuvant (Freund ' s complete adjuvant), are purchased Flower bud Deco skill Development Co., Ltd is won in Beijing.Positive control：Methotrexate (MTX) (methotrexat, MTX).Test medicine：It surveys Try COMPOUNDS EXAMPLE 7 and embodiment 22.
Preparation method：Face the used time and first prepare 0.2%CMC-Na+0.1%Tween-80 sterile waters as solvent, add in tested Compound is made into required concentration, ultrasonic mixing.
Test method：
CIA models：Chicken collagen and isometric Freund's complete adjuvant is fully emulsified, it is subcutaneous in rat root of the tail portion at 0 day Injection carries out sensitization (250 μ L/ are only), carries out booster immunization then at root of the tail portion injection (100 μ L/ are only) within the 7th day.In arthritic After (the about the 13rd day), rat is randomly divided into 4 groups, every group 8.Start to be administered within the 14th day after first immunisation, successive administration 14 My god.Rat four limbs are visually observed, 0-4 grades of scorings are carried out to arthritic severity：0=is normal；1=light symptoms, but ankle There is phenomena such as red and swollen in joint or wrist；2=ankle-joints or wrist moderate redness phenomenon；The entire pawls of 3=are all tight including toe (finger) Weight is red and swollen；4=joints serious swelling and with dysfunction；Every mouse highest scoring is 16 points.Animal hind leg foot is measured simultaneously Toe thickness and sufficient volume.
Drug therapy：Gavage 7,40mg/kg, 2 times/day of COMPOUNDS EXAMPLE；COMPOUNDS EXAMPLE 22,40mg/kg is gavaged, 2 times/day.Positive control is injected intraperitoneally, 2 times a week using MTX 5mg/kg.By the use of gavaging solvent as negative control.After administration Experimental result see the table below (table 7) compared with data before administration within 14 days：
Efficacy data in arthritis (CIA) model that 7 compound of table is induced in anti-rat collagen albumen
Experimental result is shown：
1st, compared with solvent group, rat arthritis swelling can significantly be inhibited when gavaging COMPOUNDS EXAMPLE 7 (40mg/kg) Degree, the inhibiting rate of indices are superior to positive control medicine methotrexate (MTX)；It is right to gavage COMPOUNDS EXAMPLE 22 (40mg/kg) Rat arthritis morbidity also has certain inhibitory action；
2nd, compared with solvent group, the weight of animals is mitigated methotrexate (MTX) administration group, and it is big to testing to reflect methotrexate (MTX) Mouse has certain toxicity.And test COMPOUNDS EXAMPLE 7 and 22 groups of rat body weight increases are superior to solvent group, prompt compound real Example 7 and 22 is applied without overt toxicity, comprehensive drug/safety indexes of COMPOUNDS EXAMPLE 7 are better than positive control medicine MTX。

Claims (22)

1. a kind of compound of general formula (I),
Or its stereoisomer or pharmaceutically acceptable salt,
Wherein,
R1For halogen or C1-C6 alkyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxies, C1-C6 halogen Substituted alkyl, the alkyl-carbonyl of C1-C6 and C1-C6 alkyl aminos；
R3For hydrogen or halogen；
R4For hydrogen or C1-C4 alkyl；
X is NH, O or S；
Y is CO or S (O)2；
Z is covalent bond, CH2Or (CH2)2；
N is 1 to 4 integer；
Ring A is phenyl ring, pyridine ring or piperidine ring.
2. general formula (I) compound according to claim 1, wherein：
R1For halogen or C1-C6 alkyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, fluorine, methyl, ethyl, methoxyl group, difluoromethyl, fluoroform Base, acetyl group and dimethylamino；
R3For hydrogen or halogen；
R4For hydrogen or methyl；
X is NH or O；
Y is CO or S (O)2；
Z is covalent bond, CH2Or (CH2)2；
N is 1 to 4 integer；
Ring A is phenyl ring, pyridine ring or piperidine ring.
3. general formula (I) compound according to claim 1, wherein：
R1For halogen or C1-C6 alkyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, fluorine, methyl, ethyl, methoxyl group, difluoromethyl, fluoroform Base, acetyl group and dimethylamino；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is 1 to 4 integer；
Ring A is phenyl ring, pyridine ring.
4. general formula (I) compound according to claim 1, wherein：
R1For chlorine, fluorine or methyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, fluorine, methyl, ethyl, methoxyl group, difluoromethyl, fluoroform Base, acetyl group and dimethylamino；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is 1 to 4 integer；
Ring A is phenyl ring.
5. general formula (I) compound according to claim 1, wherein：
R1For chlorine；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, fluorine, methyl, ethyl, methoxyl group, difluoromethyl, fluoroform Base, acetyl group and dimethylamino；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is 1 to 4 integer；
Ring A is phenyl ring.
6. general formula (I) compound according to claim 1, wherein：
R1For chlorine；
R2For one or more substituent groups, selected from cyano, fluorine and trifluoromethyl；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is equal to 1；
Ring A is phenyl ring.
7. general formula (I) compound according to claim 1, wherein：
R1For chlorine；
R2For one or more substituent groups, selected from cyano；
R3For hydrogen or fluorine；
R4For methyl；
X is NH；
Y is CO；
Z is covalent bond；
N is equal to 1；
Ring A is phenyl ring.
8. compound according to claim 1, wherein the compound is selected from：
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- cyanogen Yl-benzamide；
N- (3- (2- (3- acrylamido -4- fluoro-phenyls amino) -5- chlorine pyrimidine radicals -4- amino) propyl) -4- trifluoromethylbenzenes Amide；
N- (3- (2- (3- acrylamido -4- fluoro-phenyls amino) -5- chlorine pyrimidine radicals -4- amino) propyl) -4- fluorobenzoyls Amine；The fluoro- N- of 4- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidine base -4- amino) propyl) Benzamide；
N- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidine base -4- amino) propyl) -4- Trifluoromethyl benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- three Methyl fluoride benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- fluorine Benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -1- first Phenylpiperidines base -4- formamides；
N- (3- (2- (3- acrylamido -4- Fluorophenylaminos) -5- chlorine pyrimidine radicals -4- amino) propyl) -4- Cyanophenacyls Amine；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- two Methylamine yl-benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -2,4, 6- benzamide trifluoroacetates；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- first Oxybenzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -6- cyanogen Base niacinamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- hydroxyls Yl-benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- cyanogen Base -2- fluorobenzamides；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- cyanogen Base -3- fluorobenzamides；
4- cyano-N- (3- (2- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) -5- methylpyrimidine base -4- amino) third Base)-benzamide；
4- cyano-N- (3- (the fluoro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) third Base) benzamide；
N- (5- (the chloro- 4- of 5- (3- (2- (4- cyano-phenyls) acetylamino) propylcarbamic) pyrimidine radicals -2- amino) -2- fluorobenzene Base)-N- methylacryloyls；
N- (5- (the chloro- 4- of 5- (3- (4- cyanophenyl sulfonamides base) propylcarbamic) pyrimidine radicals -2- amino) -2- fluorophenyls)-N- Methylacryloyl；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- oxygroups) propyl) -4- cyanogen Yl-benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl)-different cigarette Amide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- second Yl-benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- first Yl-benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) benzoyl Amine；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -3- three Methyl fluoride benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -3- cyanogen Yl-benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -3- is fluoro- 4- trifluoromethyl benzamides；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -2,3, 4,5- tetrafluorobenzamides；
4- acetyl group-N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) third Base) benzamide；
N- (3- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) propyl) -4- two Methyl fluoride benzamide；With
N- (6- (the chloro- 2- of 5- (the fluoro- 3- of 4- (N methacrylamide base) phenyl amino) pyrimidine radicals -4- amino) hexyl) -4- cyanogen Yl-benzamide.
9. the method for logical formula (I) compound as described in claim 1 is prepared, including making logical formula (IV) compound
With logical formula (V) compound
Reaction forms logical formula (I) compound under organic solvent and catalyst action, wherein
R1For halogen or C1-C6 alkyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxies, C1-C6 halogen Substituted alkyl, the alkyl-carbonyl of C1-C6 and C1-C6 alkyl aminos；
R3For hydrogen or halogen；
R4For hydrogen or C1-C4 alkyl；
X is NH, O or S；
Y is CO or S (O)2；
Z is covalent bond, CH2Or (CH2)2；
N is 1 to 4 integer；
Ring A is phenyl ring, pyridine ring or piperidine ring.
10. the preparation method described in claim 9, wherein the catalyst, selected from trifluoroacetic acid, hydrochloric acid and methanesulfonic acid.
11. the preparation method described in claim 9, wherein the organic solvent is selected from isopropanol and n-butanol.
12. the method for logical formula (IV) compound is prepared,
Including making logical formula (III) compound
With logical formula (II) compound
Reaction forms logical formula (IV) compound under the action of organic solvent and alkali, wherein
R1For halogen or C1-C6 alkyl；
R2For one or more substituent groups, selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxies, C1-C6 halogen Substituted alkyl, the alkyl-carbonyl of C1-C6 and C1-C6 alkyl aminos；
X is NH or O；
Y is CO or S (O)2；
Z is covalent bond, CH2Or (CH2)2；
N is 1 to 4 integer；
Ring A is phenyl ring, pyridine ring or piperidine ring.
13. preparation method as claimed in claim 12, wherein the alkali is selected from triethylamine and diisopropyl ethyl amine.
14. preparation method as claimed in claim 9, wherein the organic solvent is selected from ethyl alcohol, methanol and n-butanol.
15. a kind of pharmaceutical composition for treating with the relevant disease of JAK3 and/or JAK1 abnormal kinases, it includes Logical formula (I) compound described in claim 1 is as active ingredient and pharmaceutically acceptable auxiliaries.
16. pharmaceutical composition according to claim 15, it includes logical formula (I) compound conducts described in claim 1 Active ingredient and pharmaceutical acceptable carrier or diluent.
17. pharmaceutical composition according to claim 15 is tablet, capsule, pulvis, syrup, liquor, suspending agent, pin Agent or the dosage form of paste.
18. any one of claim 1 to 8 compound is being prepared for treating or preventing autoimmune disease, inflammatory disease Disease, cancer, myeloproliferative disease, bone-resorbing disease or organ-graft refection's disease drug in application.
19. any one of claim 1 to 8 compound prepare for treat or prevent rheumatoid arthritis, psoriasis, gram Sieve grace disease, systemic loupus erythematosus, multiple sclerosis, Type I diabetes, anaphylactia, chronic obstructive pulmonary disease, asthma, Leukaemia, lymphoma disease drug in application.
20. pharmaceutical composition any one of claim 15 to 17 is preparing for treating or preventing autoimmune disease Disease, diseases associated with inflammation, cancer, myeloproliferative disease, bone-resorbing disease and organ-graft refection's disease drug in should With.
21. pharmaceutical composition any one of claim 15 to 17 is preparing for treating or preventing rheumatoid joint Inflammation, psoriasis, Crohn disease, systemic loupus erythematosus, multiple sclerosis, Type I diabetes, anaphylactia, chronic obstruction Property tuberculosis, asthma, leukaemia, lymphoma disease drug in application.
22. pharmaceutical composition according to claim 17, wherein the unit dose of the dosage form for 0.0001~ 200mg。
CN201410471468.9A 2014-09-16 2014-09-16 The alternatively preparation method and applications of the heteroaromatic compounds of property JAK3 and/or JAK1 kinase inhibitors Active CN105399685B (en)

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CN201410471468.9A CN105399685B (en) 2014-09-16 2014-09-16 The alternatively preparation method and applications of the heteroaromatic compounds of property JAK3 and/or JAK1 kinase inhibitors
BR112017005113-3A BR112017005113B1 (en) 2014-09-16 2015-09-14 COMPOUND OF GENERAL FORMULA (I), METHOD FOR PREPARING THE COMPOUND OF GENERAL FORMULA (I), METHOD FOR PREPARING A COMPOUND OF GENERAL FORMULA (IV), PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF DISEASES RELATED TO ABNORMAL ACTIVITIES OF JAK3 AND/OR JAK1 KINASES , USE OF THE COMPOUND, AND USE OF THE PHARMACEUTICAL COMPOSITION
PCT/CN2015/089499 WO2016041472A1 (en) 2014-09-16 2015-09-14 Preparation method for aromatic heterocyclic compound used as selective jak3 and/or jak1 kinase inhibitor and application of aromatic heterocyclic compound
AU2015317937A AU2015317937B2 (en) 2014-09-16 2015-09-14 Preparation method for aromatic heterocyclic compound used as selective JAK3 and/or JAK1 kinase inhibitor and application of aromatic heterocyclic compound
US15/510,758 US10011571B2 (en) 2014-09-16 2015-09-14 Preparation method for aromatic heterocyclic compound used as selective JAK3 and/or JAK1 kinase inhibitor and application of aromatic heterocyclic compound
RU2017112299A RU2671195C2 (en) 2014-09-16 2015-09-14 Method for obtaining aromatic heterocyclic compound used as selective inhibitor of kinase jak1 and application thereof
LTEP15842179.2T LT3196194T (en) 2014-09-16 2015-09-14 Pyrimidine derivatives useful as selective jak3 and/or jak1 inhibitors
ES15842179T ES2754403T3 (en) 2014-09-16 2015-09-14 Pririmidine derivatives useful as selective inhibitors of JAK3 and / or JAK1
EP15842179.2A EP3196194B1 (en) 2014-09-16 2015-09-14 Pyrimidine derivatives useful as selective jak3 and/or jak1 inhibitors
SI201530965T SI3196194T1 (en) 2014-09-16 2015-09-14 Pyrimidine derivatives useful as selective jak3 and/or jak1 inhibitors
DK15842179T DK3196194T3 (en) 2014-09-16 2015-09-14 PYRIMIDINE DERIVATIVES USED AS SELECTIVE JAK3 AND / OR JAK1 INHIBITORS
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JP2017533675A JP6516305B2 (en) 2014-09-16 2015-09-14 Process for the preparation of heteroaromatic compounds which are selective JAK3 and / or JAK1 kinase inhibitors and their use
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